bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Biases and Democratic Anxiety: A Comment on Little and Meng (2023)
Authors: Treisman Daniel
Published: January 2024

In their timely article, Andrew Little and Anne Meng make an important point. Despite widespread alarm over democratic backsliding, objective evidence suggests that the scale of the phenomenon is much more limited than many seem to think. Recent power holders around the world have not been entrenching themselves more effectively than in the past. Incumbents continue to lose elections about as often as they used to, and those who win have not been doing so by larger margins. Opposition parties are allowed to compete about as frequently today as 10 or 20 years ago. Moreover, there has been no increase in leaders’ ability to evade term limits.
Hepatocyte growth factor as indicator for subclinical	atherosclerosis
Authors: Sommer Philip , Schreinlechner Michael , Noflatscher Maria , Engl Clarisse , Lener Daniela , Theurl Markus , Kirchmair Rudolf , Marschang Peter
Published: January 2024

Summary: Background: Hepatocyte growth factor (HGF) is a pleiotropic cytokine mainly produced by mesenchymal cells. After endothelial damage by oxidized low-density lipoprotein (LDL), HGF is produced and released into the circulation in response. Due to this mechanism HGF has been proposed as possible clinical biomarker for clinical as well as subclinical atherosclerosis. Patients and methods: The conducted study is an observational, single centre, cohort study, including 171 patients with at least one cardiovascular risk factor or already established cardiovascular disease (CVD). Each patient underwent 3D plaque volumetry of the carotid and femoral arteries as well as physical examination and record of the medical history. Additionally, plasma HGF and further laboratory parameters like high sensitivity C-reactive protein and LDL-cholesterol were determined. Results: 169 patients were available for statistical analysis. In bivariate correlation, HGF showed a highly significant correlation with total plaque volume (TPV, r=0.48; p<0.001). In receiver operating characteristic (ROC) analysis for high TPV, HGF showed an area under the curve (AUC) of 0.68 (CI 95%: 0.59–0.77, p<0.001) with a sensitivity of 78% and a specificity of 52% to predict high TPV at a cut-off of 959 ng/ml. In the ROC-analysis for the presence of CVD, HGF demonstrated an AUC of 0.65 (95% CI 0.55–0.73; p=0.01) with a sensitivity of 77% and a specificity of 52%. Conclusions: Higher plasma levels of HGF are associated with higher atherosclerotic plaque volume as measured by 3D-ultrasound.
Open Science in der deutschsprachigen Sportpsychologie
Authors: Ennigkeit Fabienne , Englert Chris , Stehle Juliane , Schweizer Geoffrey
Published: January 2024

Zusammenfassung: Ziel des vorliegenden Artikels ist es, die Verbreitung unterschiedlicher Open-Science-Praktiken in Publikationen der deutschsprachigen Sportpsychologie zu untersuchen. Dazu wurde die in den Jahren 2020 und 2021 von Arbeitsgruppen in Deutschland, Österreich und der Schweiz publizierte sportpsychologische Literatur analysiert. Die Ergebnisse legen nahe, dass verschiedene Open-Science-Praktiken unterschiedlich häufig genutzt werden: Während beispielsweise knapp 50 % der analysierten Artikel in Open-Access-Modellen publiziert wurden, wurde in nur 2,4 % der Artikel der zur Analyse verwendete Code mitveröffentlicht. Zukünftige Diskussionen um Open-Science-Praktiken in der Sportpsychologie und Maßnahmen zu ihrer Förderung könnten somit von einem differenzierteren Umgang mit einzelnen Praktiken profitieren, statt Bezug auf das übergeordnete Konzept „Open Science“ zu nehmen. Die vorliegenden Daten können zudem als Grundlage für weitere Diskussionen zu Open Science in der deutschsprachigen Sportpsychologie dienen sowie als Vergleichsstandard für zukünftige Entwicklungen genutzt werden.
Control of Stability and Relative Humidity in the Radiative‐Convective Equilibrium Model Intercomparison Project
Authors: Wing Allison A. , Singh Martin S.
Published: January 2024

The Radiative‐Convective Equilibrium Model Intercomparison Project (RCEMIP) exhibits a large spread in the simulated climate across models, including in profiles of buoyancy and relative humidity. Here we use simple theory to understand the control of stability, relative humidity, and their responses to warming. Across the RCEMIP ensemble, temperature profiles are systematically cooler than a moist adiabat, and convective available potential energy (CAPE) increases with warming at a rate greater than that expected from the Clausius‐Clapeyron relation. There is higher CAPE (greater instability) in models that are on average moister in the lower‐troposphere. To more explicitly evaluate the drivers of the intermodel spread, we use simple theory to estimate values of entrainment and precipitation efficiency (PE) given the simulated values of CAPE and lower‐tropospheric relative humidity. We then decompose the intermodel spread in CAPE and relative humidity (and their responses to warming) into contributions from variability in entrainment, PE, the temperature of the convecting top, and the inverse water vapor scale height. Model‐to‐model variation in entrainment is a dominant source of intermodel spread in CAPE and its changes with warming, while variation in PE is the dominant source of intermodel spread in relative humidity. We also decompose the magnitude of the CAPE increase with warming and find that atmospheric warming itself contributes most strongly to the CAPE increase, but the indirect effect of increases in the water vapor scale height with warming also contribute to increasing CAPE beyond that expected from Clausius‐Clapeyron.
Acoustofluidic separation of prolate and spherical micro-objects
Authors: Khan Muhammad Soban , Ali Mushtaq , Lee Song Ha , Jang Keun Young , Lee Seong Jae , Park Jinsoo
Published: January 2024

Most microfluidic separation techniques rely largely on object size as a separation marker. The ability to separate micro-objects based on their shape is crucial in various biomedical and chemical assays. Here, we develop an on-demand, label-free acoustofluidic method to separate prolate ellipsoids from spherical microparticles based on traveling surface acoustic wave-induced acoustic radiation force and torque. The freely rotating non-spherical micro-objects were aligned under the progressive acoustic field by the counterrotating radiation torque, and the major axis of the prolate ellipsoids was parallel to the progressive wave propagation. The specific alignment of the ellipsoidal particles resulted in a reduction in the cross-sectional area perpendicular to the wave propagation. As a consequence, the acoustic backscattering decreased, resulting in a decreased magnitude of the radiation force. Through the variation in radiation force, which depended on the micro-object morphology enabled the acoustofluidic shape-based separation. We conducted numerical simulations for the wave scattering of spherical and prolate objects to elucidate the working mechanism underlying the proposed method. A series of experiments with polystyrene microspheres, prolate ellipsoids, and peanut-shaped microparticles were performed for validation. Through quantitative analysis of the separation efficiency, we confirmed the high purity and high recovery rate of the proposed acoustofluidic shape-based separation of micro-objects. As a bioparticle, we utilize Thalassiosira eccentrica to perform shape-based separation, as the species has a variety of potential applications in drug delivery, biosensing, nanofabrication, bioencapsulation and immunoisolation.
Low androgen signaling rescues genome integrity with innate immune response by reducing fertility in humans
Authors: Zimmer J. , Mueller L. , Frank-Herrmann P. , Rehnitz J. , Dietrich J. E. , Bettendorf M. , Strowitzki T. , Krivega M.
Published: January 2024

Development of the gonads under complex androgen regulation is critical for germ cells specification. In this work we addressed the relationship between androgens and genomic integrity determining human fertility. We used different study groups: individuals with Differences of Sex Development (DSD), including Complete Androgen Insensitivity Syndrome (CAIS) due to mutated androgen receptor (AR), and men with idiopathic nonobstructive azoospermia. Both showed genome integrity status influenced by androgen signaling via innate immune response activation in blood and gonads. Whole proteome analysis connected low AR to interleukin-specific gene expression, while compromised genome stability and tumorigenesis were also supported by interferons. AR expression was associated with predominant DNA damage phenotype, that eliminated AR-positive Sertoli cells as the degeneration of gonads increased. Low AR contributed to resistance from the inhibition of DNA repair in primary leukocytes. Downregulation of androgen promoted apoptosis and specific innate immune response with higher susceptibility in cells carrying genomic instability.
Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models
Authors: Rodriguez-Berriguete Gonzalo , Puliyadi Rathi , Machado Nicole , Barberis Alessandro , Prevo Remko , McLaughlin Martin , Buffa Francesca M. , Harrington Kevin J. , Higgins Geoff S.
Published: January 2024

Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
Amyloid aggregates induced by the p53-R280T mutation lead to loss of p53 function in nasopharyngeal carcinoma
Authors: Li Jingzhi , Guo Ming , Chen Lin , Chen Zhuchu , Fu Ying , Chen Yongheng
Published: January 2024

Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast Asia, especially in South China. The pathogenesis of NPC is complex, and genetic alterations of tumor suppressors and proto-oncogenes play important roles in NPC carcinogenesis. p53 is unexpectedly highly expressed in NPC and possesses an uncommon mutation of R280T, which is different from a high frequency of hotspot mutations or low expression in other tumors. However, the mechanism of p53 loss of function and its correlation with R280T in NPC are still unclear. In this study, p53 amyloid aggregates were found to be widespread in NPC and can be mainly induced by the R280T mutation. Aggregated p53-R280T impeded its entry into the nucleus and was unable to initiate the transcription of downstream target genes, resulting in decreased NPC cell cycle arrest and apoptosis. In addition, NPC cells with p53-R280T amyloid aggregates also contributed aggressively to tumor growth in vivo. Transcriptome analysis suggested that p53 amyloid aggregation dysregulated major signaling pathways associated with the cell cycle, proliferation, apoptosis, and unfolded protein response (UPR). Further studies revealed that Hsp90, as a key molecular chaperone in p53 folding, was upregulated in NPC cells with p53-R280T aggregation, and the upregulated Hsp90 facilitated p53 aggregation in turn, forming positive feedback. Therefore, Hsp90 inhibitors could dissociate p53-R280T aggregation and restore the suppressor function of p53 in vitro and in vivo. In conclusion, our study demonstrated that p53-R280T may misfold to form aggregates with the help of Hsp90, resulting in the inability of sequestered p53 to initiate the transcription of downstream target genes. These results revealed a new mechanism for the loss of p53 function in NPC and provided novel mechanistic insight into NPC pathogenesis.
Ferric reduction by a CYBDOM protein counteracts increased iron availability in root meristems induced by phosphorus deficiency
Authors: Maniero Rodolfo A. , Picco Cristiana , Hartmann Anja , Engelberger Felipe , Gradogna Antonella , Scholz-Starke Joachim , Melzer Michael , Künze Georg , Carpaneto Armando , von Wirén Nicolaus , Giehl Ricardo F. H.
Published: January 2024

To mobilize sparingly available phosphorus (P) in the rhizosphere, many plant species secrete malate to release P sorbed onto (hydr)oxides of aluminum and iron (Fe). In the presence of Fe, malate can provoke Fe over-accumulation in the root apoplast, triggering a series of events that inhibit root growth. Here, we identified HYPERSENSITIVE TO LOW P1 (HYP1), a CYBDOM protein constituted of a DOMON and a cytochrome b561 domain, as critical to maintain cell elongation and meristem integrity under low P. We demonstrate that HYP1 mediates ascorbate-dependent trans-plasma membrane electron transport and can reduce ferric and cupric substrates in Xenopus laevis oocytes and in planta. HYP1 expression is up-regulated in response to P deficiency in the proximal zone of the root apical meristem. Disruption of HYP1 leads to increased Fe and callose accumulation in the root meristem and causes significant transcriptional changes in roots. We further demonstrate that HYP1 activity overcomes malate-induced Fe accumulation, thereby preventing Fe-dependent root growth arrest in response to low P. Collectively, our results uncover an ascorbate-dependent metalloreductase that is critical to protect root meristems of P-deficient plants from increased Fe availability and provide insights into the physiological function of the yet poorly characterized but ubiquitous CYBDOM proteins.
Distributed quantum sensing of multiple phases with fewer photons
Authors: Kim Dong-Hyun , Hong Seongjin , Kim Yong-Su , Kim Yosep , Lee Seung-Woo , Pooser Raphael C. , Oh Kyunghwan , Lee Su-Yong , Lee Changhyoup , Lim Hyang-Tag
Published: January 2024

Distributed quantum metrology has drawn intense interest as it outperforms the optimal classical counterparts in estimating multiple distributed parameters. However, most schemes so far have required entangled resources consisting of photon numbers equal to or more than the parameter numbers, which is a fairly demanding requirement as the number of nodes increases. Here, we present a distributed quantum sensing scenario in which quantum-enhanced sensitivity can be achieved with fewer photons than the number of parameters. As an experimental demonstration, using a two-photon entangled state, we estimate four phases distributed 3 km away from the central node, resulting in a 2.2 dB sensitivity enhancement from the standard quantum limit. Our results show that the Heisenberg scaling can be achieved even when using fewer photons than the number of parameters. We believe our scheme will open a pathway to perform large-scale distributed quantum sensing with currently available entangled sources.
Significantly wetter or drier future conditions for one to two thirds of the world’s population
Authors: Trancoso Ralph , Syktus Jozef , Allan Richard P. , Croke Jacky , Hoegh-Guldberg Ove , Chadwick Robin
Published: January 2024

Future projections of precipitation are uncertain, hampering effective climate adaptation strategies globally. Our understanding of changes across multiple climate model simulations under a warmer climate is limited by this lack of coherence across models. Here, we address this challenge introducing an approach that detects agreement in drier and wetter conditions by evaluating continuous 120-year time-series with trends, across 146 Global Climate Model (GCM) runs and two elevated greenhouse gas (GHG) emissions scenarios. We show the hotspots of future drier and wetter conditions, including regions already experiencing water scarcity or excess. These patterns are projected to impact a significant portion of the global population, with approximately 3 billion people (38% of the world’s current population) affected under an intermediate emissions scenario and 5 billion people (66% of the world population) under a high emissions scenario by the century’s end (or 35-61% using projections of future population). We undertake a country- and state-level analysis quantifying the population exposed to significant changes in precipitation regimes, offering a robust framework for assessing multiple climate projections.
Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Authors: Sharma Pankaj , Maklashina Elena , Voehler Markus , Balintova Sona , Dvorakova Sarka , Kraus Michal , Hadrava Vanova Katerina , Nahacka Zuzana , Zobalova Renata , Boukalova Stepana , Cunatova Kristyna , Mracek Tomas , Ghayee Hans K. , Pacak Karel , Rohlena Jakub , Neuzil Jiri , Cecchini Gary , Iverson T. M.
Published: January 2024

Complex II (CII) activity controls phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, cancer metabolism, immune activation, and ischemia-reperfusion injury. CII activity can be regulated at the level of assembly, a process that leverages metastable assembly intermediates. The nature of these intermediates and how CII subunits transfer between metastable complexes remains unclear. In this work, we identify metastable species containing the SDHA subunit and its assembly factors, and we assign a preferred temporal sequence of appearance of these species during CII assembly. Structures of two species show that the assembly factors undergo disordered-to-ordered transitions without the appearance of significant secondary structure. The findings identify that intrinsically disordered regions are critical in regulating CII assembly, an observation that has implications for the control of assembly in other biomolecular complexes.
Methane-hydrogen-rich fluid migration may trigger seismic failure in subduction zones at forearc depths
Authors: Giuntoli Francesco , Menegon Luca , Siron Guillaume , Cognigni Flavio , Leroux Hugues , Compagnoni Roberto , Rossi Marco , Vitale Brovarone Alberto
Published: January 2024

Metamorphic fluids, faults, and shear zones are carriers of carbon from the deep Earth to shallower reservoirs. Some of these fluids are reduced and transport energy sources, like H2and light hydrocarbons. Mechanisms and pathways capable of transporting these deep energy sources towards shallower reservoirs remain unidentified. Here we present geological evidence of failure of mechanically strong rocks due to the accumulation of CH4-H2-rich fluids at deep forearc depths, which ultimately reached supralithostatic pore fluid pressure. These fluids originated from adjacent reduction of carbonates by H2-rich fluids during serpentinization at eclogite-to-blueschist-facies conditions. Thermodynamic modeling predicts that the production and accumulation of CH4-H2-rich aqueous fluids can produce fluid overpressure more easily than carbon-poor and CO2-rich aqueous fluids. This study provides evidence for the migration of deep Earth energy sources along tectonic discontinuities, and suggests causal relationships with brittle failure of hard rock types that may trigger seismic activity at forearc depths.
Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment
Authors: Villa Matteo , Sanin David E. , Apostolova Petya , Corrado Mauro , Kabat Agnieszka M. , Cristinzio Carmine , Regina Annamaria , Carrizo Gustavo E. , Rana Nisha , Stanczak Michal A. , Baixauli Francesc , Grzes Katarzyna M. , Cupovic Jovana , Solagna Francesca , Hackl Alexandra , Globig Anna-Maria , Hässler Fabian , Puleston Daniel J. , Kelly Beth , Cabezas-Wallscheid Nina , Hasselblatt Peter , Bengsch Bertram , Zeiser Robert , Sagar  , Buescher Joerg M. , Pearce Edward J. , Pearce Erika L.
Published: January 2024

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Tracking a spin-polarized superconducting bound state across a quantum phase transition
Authors: Karan Sujoy , Huang Haonan , Ivanovic Alexander , Padurariu Ciprian , Kubala Björn , Kern Klaus , Ankerhold Joachim , Ast Christian R.
Published: January 2024

The magnetic exchange coupling between magnetic impurities and a superconductor induce so-called Yu-Shiba-Rusinov (YSR) states which undergo a quantum phase transition (QPT) upon increasing the exchange interaction beyond a critical value. While the evolution through the QPT is readily observable, in particular if the YSR state features an electron-hole asymmetry, the concomitant change in the ground state is more difficult to identify. We use ultralow temperature scanning tunneling microscopy to demonstrate how the change in the YSR ground state across the QPT can be directly observed for a spin-1/2 impurity in a magnetic field. The excitation spectrum changes from featuring two peaks in the doublet (free spin) state to four peaks in the singlet (screened spin) ground state. We also identify a transition regime, where the YSR excitation energy is smaller than the Zeeman energy. We thus demonstrate a straightforward way for unambiguously identifying the ground state of a spin-1/2 YSR state.
Unusual flexibility of transparent poly(methylsilsesquioxane) aerogels by surfactant-induced mesoscopic fiber-like assembly
Authors: Ueoka Ryota , Hara Yosuke , Maeno Ayaka , Kaji Hironori , Nakanishi Kazuki , Kanamori Kazuyoshi
Published: January 2024

High-performance thermal insulators represented by aerogels are regarded as one of the most promising materials for energy savings. However, significantly low mechanical strength has been a barrier for aerogels to be utilized in various social domains such as houses, buildings, and industrial plants. Here, we report a synthetic strategy to realize highly transparent aerogels with unusually high bending flexibility based on poly(methylsilsesquioxane) (PMSQ) network. We have constructed mesoscopic fine fiber-like structures of various sizes in PMSQ gels by the combination of phase separation suppression by tetramethylammonium hydroxide (TMAOH) and mesoscopic fiber-like assembly by nonionic poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-b-PPO-b-PEO) type surfactant. The optimized mesoscale structures of PMSQ gels have realized highly transparent and resilient monolithic aerogels with much high bendability compared to those reported in previous works. This work will provide a way to highly insulating materials with glasslike transparency and high mechanical flexibility.
Commensal lifestyle regulated by a negative feedback loop between Arabidopsis ROS and the bacterial T2SS
Authors: Entila Frederickson , Han Xiaowei , Mine Akira , Schulze-Lefert Paul , Tsuda Kenichi
Published: January 2024

Despite the plant health-promoting effects of plant microbiota, these assemblages also comprise potentially detrimental microbes. How plant immunity controls its microbiota to promote plant health under these conditions remains largely unknown. We find that commensal bacteria isolated from healthy Arabidopsis plants trigger diverse patterns of reactive oxygen species (ROS) production dependent on the immune receptors and completely on the NADPH oxidase RBOHD that selectively inhibited specific commensals, notably Xanthomonas L148. Through random mutagenesis, we find that L148 gspE, encoding a type II secretion system (T2SS) component, is required for the damaging effects of Xanthomonas L148 on rbohD mutant plants. In planta bacterial transcriptomics reveals that RBOHD suppresses most T2SS gene expression including gspE. L148 colonization protected plants against a bacterial pathogen, when gspE was inhibited by ROS or mutation. Thus, a negative feedback loop between Arabidopsis ROS and the bacterial T2SS tames a potentially detrimental leaf commensal and turns it into a microbe beneficial to the host.
Wide-range soft anisotropic thermistor with a direct wireless radio frequency interface
Authors: Wagih Mahmoud , Shi Junjie , Li Menglong , Komolafe Abiodun , Whittaker Thomas , Schneider Johannes , Kumar Shanmugam , Whittow William , Beeby Steve
Published: January 2024

Temperature sensors are one of the most fundamental sensors and are found in industrial, environmental, and biomedical applications. The traditional approach of reading the resistive response of Positive Temperature Coefficient thermistors at DC hindered their adoption as wide-range temperature sensors. Here, we present a large-area thermistor, based on a flexible and stretchable short carbon fibre incorporated Polydimethylsiloxane composite, enabled by a radio frequency sensing interface. The radio frequency readout overcomes the decades-old sensing range limit of thermistors. The composite exhibits a resistance sensitivity over 1000 °C−1, while maintaining stability against bending (20,000 cycles) and stretching (1000 cycles). Leveraging its large-area processing, the anisotropic composite is used as a substrate for sub-6 GHz radio frequency components, where the thermistor-based microwave resonators achieve a wide temperature sensing range (30 to 205 °C) compared to reported flexible temperature sensors, and high sensitivity (3.2 MHz/°C) compared to radio frequency temperature sensors. Wireless sensing is demonstrated using a microstrip patch antenna based on a thermistor substrate, and a battery-less radio frequency identification tag. This radio frequency-based sensor readout technique could enable functional materials to be directly integrated in wireless sensing applications.
De novo biosynthesis of antiarrhythmic alkaloid ajmaline
Authors: Guo Jun , Gao Di , Lian Jiazhang , Qu Yang
Published: January 2024

The antiarrhythmic drug ajmaline is a monoterpenoid indole alkaloid (MIA) isolated from the Ayurvedic plant Rauvolfia serpentina (Indian Snakeroot). Research into the biosynthesis of ajmaline and another renowned MIA chemotherapeutic drug vinblastine has yielded pivotal advancements in the fields of plant specialized metabolism and engineering over recent decades. While the majority of vinblastine biosynthesis has been recently elucidated, the quest for comprehending ajmaline biosynthesis remains incomplete, marked by the absence of two critical enzymes. Here, we show the discovery and characterization of these two elusive reductases, alongside the identification of two physiologically relevant esterases that complete the biosynthesis of ajmaline. We show that ajmaline biosynthesis proceeds with vomilenine 1,2(R)-reduction followed by its 19,20(S)-reduction. This process is further modulated by two root-expressing esterases that deacetylate 17-O-acetylnorajmaline. Expanding upon the successful completion of the ajmaline biosynthetic pathway, we engineer the de novo biosynthesis of ajmaline in Baker’s yeast.
Immunological shifts during early-stage Parkinson’s disease identified with DNA methylation data on longitudinally collected blood samples
Authors: Pike Steven C. , Havrda Matthew , Gilli Francesca , Zhang Ze , Salas Lucas A.
Published: January 2024

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the United States. Decades before motor symptoms manifest, non-motor symptoms such as hyposmia and rapid eye movement (REM) sleep behavior disorder are highly predictive of PD. Previous immune profiling studies have identified alterations to the proportions of immune cells in the blood of clinically defined PD patients. However, it remains unclear if these phenotypes manifest before the clinical diagnosis of PD. We utilized longitudinal DNA methylation (DNAm) microarray data from the Parkinson’s Progression Marker’s Initiative (PPMI) to perform immune profiling in clinically defined PD and prodromal PD patients (Prod). We identified previously reported changes in neutrophil, monocyte, and T cell numbers in PD patients. Additionally, we noted previously unrecognized decreases in the naive B cell compartment in the defined PD and Prod patient group. Over time, we observed the proportion of innate immune cells in PD blood increased, but the proportion of adaptive immune cells decreased. We identified decreases in T and B cell subsets associated with REM sleep disturbances and early cognitive decline. Lastly, we identified increases in B memory cells associated with both genetic (LRRK2 genotype) and infectious (cytomegalovirus seropositivity) risk factors of PD. Our analysis shows that the peripheral immune system is dynamic as the disease progresses. The study provides a platform to understand how and when peripheral immune alterations occur in PD and whether intervention at particular stages may be therapeutically advantageous.
A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease
Authors: Fu YuHong , Pickford Russell , Galper Jasmin , Phan Katherine , Wu Ping , Li Hongyun , Kim Young-Bum , Dzamko Nicolas , Halliday Glenda M. , Kim Woojin Scott
Published: January 2024

Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) is a lysosomal transporter that mediates the removal of excess sphingomyelin from lysosomes. We therefore investigated whether the expression levels of ABCA5 are associated with sphingomyelin levels and α-synuclein pathology in PD. Firstly, we undertook a comprehensive assessment of the six sphingolipid classes that are part of the lysosomal salvage pathway in the disease-affected amygdala and disease-unaffected visual cortex using liquid chromatography-mass spectrometry. We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the amygdala, whereas, the five other sphingolipid classes were slightly altered or unaltered. Concomitantly, the expression of ABCA5 was upregulated in the PD amygdala compared to controls and correlated strongly with sphingomyelin levels. Using neuronal cells, we further verified that the expression of ABCA5 was dependent on cellular levels of sphingomyelin. Interestingly, sphingomyelin levels were strongly associated with α-synuclein in the amygdala and were related to α-synuclein expression. Finally, we revealed that sphingomyelin levels were also increased in PD plasma compared to controls, and that five identical sphingomyelin species were increased in both the brain and the plasma. When put together, these results suggest that in regions accumulating α-synuclein in PD, ABCA5 is upregulated to reduce lysosomal sphingomyelin levels potentially as a protective measure. This process may provide new targets for therapeutic intervention and biomarker development for PD.
Hamiltonian phase error in resonantly driven CNOT gate above the fault-tolerant threshold
Authors: Wu Yi-Hsien , Camenzind Leon C. , Noiri Akito , Takeda Kenta , Nakajima Takashi , Kobayashi Takashi , Chang Chien-Yuan , Sammak Amir , Scappucci Giordano , Goan Hsi-Sheng , Tarucha Seigo
Published: January 2024

Because of their long coherence time and compatibility with industrial foundry processes, electron spin qubits are a promising platform for scalable quantum processors. A full-fledged quantum computer will need quantum error correction, which requires high-fidelity quantum gates. Analyzing and mitigating gate errors are useful to improve gate fidelity. Here, we demonstrate a simple yet reliable calibration procedure for a high-fidelity controlled-rotation gate in an exchange-always-on Silicon quantum processor, allowing operation above the fault-tolerance threshold of quantum error correction. We find that the fidelity of our uncalibrated controlled-rotation gate is limited by coherent errors in the form of controlled phases and present a method to measure and correct these phase errors. We then verify the improvement in our gate fidelities by randomized benchmark and gate-set tomography protocols. Finally, we use our phase correction protocol to implement a virtual, high-fidelity, controlled-phase gate.
Individual honey bee tracking in a beehive environment using deep learning and Kalman filter
Authors: Kongsilp Panadda , Taetragool Unchalisa , Duangphakdee Orawan
Published: January 2024

The honey bee is the most essential pollinator and a key contributor to the natural ecosystem. There are numerous ways for thousands of bees in a hive to communicate with one another. Individual trajectories and social interactions are thus complex behavioral features that can provide valuable information for an ecological study. To study honey bee behavior, the key challenges that have resulted from unreliable studies include complexity (high density of similar objects, small objects, and occlusion), the variety of background scenes, the dynamism of individual bee movements, and the similarity between the bee body and the background in the beehive. This study investigated the tracking of individual bees in a beehive environment using a deep learning approach and a Kalman filter. Detection of multiple bees and individual object segmentation were performed using Mask R-CNN with a ResNet-101 backbone network. Subsequently, the Kalman filter was employed for tracking multiple bees by tracking the body of each bee across a sequence of image frames. Three metrics were used to assess the proposed framework: mean average precision (mAP) for multiple-object detection and segmentation tasks, CLEAR MOT for multiple object tracking tasks, and MOTS for multiple object tracking and segmentation tasks. For CLEAR MOT and MOTS metrics, accuracy (MOTA and MOTSA) and precision (MOTP and MOTSP) are considered. By employing videos from a custom-designed observation beehive, recorded at a frame rate of 30 frames per second (fps) and utilizing a continuous frame rate of 10 fps as input data, our system displayed impressive performance. It yielded satisfactory outcomes for tasks involving segmentation and tracking of multiple instances of bee behavior. For the multiple-object segmentation task based on Mask R-CNN, we achieved a 0.85 mAP. For the multiple-object-tracking task with the Kalman filter, we achieved 77.48% MOTA, 79.79% MOTSP, and 79.56% recall. For the overall system for multiple-object tracking and segmentation tasks, we achieved 77.00% MOTSA, 75.60% MOTSP, and 80.30% recall.
Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: a randomized controlled pilot trial (NACTLYS)
Authors: Komakula Snigdha , Bhatia Rohit , Sahib Akhil , Upadhyay Ashish , S Leve Joseph , Garg Ajay , Y Vishnu V , Pandit Awadh Kishor , Vibha Deepti , Singh Mamta Bhushan , Tripathi Manjari , Srivastava M. V. Padma
Published: January 2024

There is a pressing clinical need for thrombolytic agents that can effectively disaggregate arterial thrombi in acute ischemic stroke without significantly increasing the risk of bleeding. This pilot study aimed to investigate the safety and efficacy of N-acetylcysteine (NAC) as an adjunctive therapy to intravenous recombinant tissue plasminogen activator (rtPA or alteplase). A randomized, open-label, blinded assessor pilot study was conducted. Patients presenting with an acute ischemic stroke within 4.5 h from onset were randomized into two groups: intravenous NAC and rtPA or rtPA alone. Primary outcomes included intracerebral hemorrhage, symptomatic intracerebral hemorrhage, extracranial bleeding, and adverse reactions. Secondary outcomes comprised major neurological improvement assessed by (National Institute of Health Stroke Scale) NIHSS at 24 h, recanalization on first run of angiography in patients who underwent thrombectomy or on repeat vascular imaging at 24 h, modified Rankin scale, and three-month mortality. Forty patients were enrolled, with 21 receiving only rtPA and 19 receiving NAC with rtPA. Baseline characteristics were comparable among groups. No significant differences were observed in adverse events (p = 0.99), intracranial hemorrhage (p = 0.21), symptomatic intracerebral hemorrhage (p = 0.47), or extracranial bleeding (p = 0.21). Median NIHSS at 24 h was significantly lower in the intervention group (p = 0.03). Functional outcomes and three-month mortality were similar between groups (p = 0.85 and p = 0.99 respectively). The co-administration of N-acetylcysteine with alteplase did not significantly alter safety profiles, morbidity, or mortality at 3 months. While no substantial differences were noted, a slightly improved early neurological outcome was observed in the intervention arm. The study's findings were constrained by a small sample size, emphasizing the necessity for future large-scale trials to comprehensively evaluate the safety and efficacy of N-acetylcysteine as a thrombolytic agent in acute ischemic stroke.

Trial Registration Clinical Trials Registry India—CTRI/2019/05/019305.
An exploratory metabolomic comparison of participants with fast or absent functional progression from 2CARE, a randomized, double-blind clinical trial in Huntington’s disease
Authors: McGarry Andrew , Hunter Krystal , Gaughan John , Auinger Peggy , Ferraro Thomas N. , Pradhan Basant , Ferrucci Luigi , Egan Josephine M. , Moaddel Ruin
Published: January 2024

Huntington’s disease (HD) is increasingly recognized for diverse pathology outside of the nervous system. To describe the biology of HD in relation to functional progression, we previously analyzed the plasma and CSF metabolome in a cross-sectional study of participants who had various degrees of functional impairment. Here, we carried out an exploratory study in plasma from HD individuals over a 3-year time frame to assess whether differences exist between those with fast or absent clinical progression. There were more differences in circulating metabolite levels for fast progressors compared to absent progressors (111 vs 20, nominal p < 0.05). All metabolite changes in faster progressors were decreases, whereas some metabolite concentrations increased in absent progressors. Many of the metabolite levels that decreased in the fast progressors were higher at Screening compared to absent progressors but ended up lower by Year 3. Changes in faster progression suggest greater oxidative stress and inflammation (kynurenine, diacylglycerides, cysteine), disturbances in nitric oxide and urea metabolism (arginine, citrulline, ornithine, GABR), lower polyamines (putrescine and spermine), elevated glucose, and deficient AMPK signaling. Metabolomic differences between fast and absent progressors suggest the possibility of predicting functional decline in HD, and possibly delaying it with interventions to augment arginine, polyamines, and glucose regulation.
Endometrial biopsy performed before the first in vitro fertilization does not impact the early pregnancy rate
Authors: Cellier Mathilde , Werlen Sophie , Lionel Mery , Genod Anne , Felloni Bertrand , Semay Tiphaine , Trombert Béatrice , Chauleur Céline , Raia-Barjat Tiphaine
Published: January 2024

Endometrial biopsy (EB) has been showed to increase the rate of clinical pregnancy in patients who underwent in vitro fertilization (IVF) failures. The purpose of this work was to assess the impact of an EB performed before the first in IVF on the early pregnancy rate. Be One study is a prospective, single-centre, randomized, open-label study. In this parallel study, patients were evenly split into two groups. In one group, patients underwent an EB between days 17 and 22 of the menstrual cycle that precedes the ovarian stimulation. In the other group (control), no EB was performed. The hCG-positive rate (early pregnancy rate) was evaluated on day 14 after the ovarian puncture. In total, 157 patients were randomized in the EB group and 154 patients were in the control group. The early pregnancy rate was 33.1% (52/157) in the EB group and 29.9% (46/154) in the control group (p = 0.54). Other parameters, including perforation, endometritis, or pain level were reassuring. An EB performed during the luteal phase of the menstrual cycle preceding the stimulation of the first IVF did not increase early pregnancy rate.
Partisan styles of self-presentation in U.S. Twitter bios
Authors: Essig Liam , DellaPosta Daniel
Published: January 2024

Political polarization in the United States goes beyond divided opinions on key political issues, extending to realms of culture, lifestyle, and social identity once thought to be apolitical. Using a sample of 1 million Twitter bios, this study investigates how users’ partisan self-presentation on social media tends to include cultural as well as political markers. Representing the text in Twitter bios as semantic networks, the study reveals clear partisan differences in how users describe themselves, even on topics that seem apolitical. Consequently, active Twitter users’ political alignments can be statistically inferred from the non-political references in their bios, even in the absence of explicitly partisan language. These findings offer further evidence of partisan polarization that is aligned with lifestyle preferences. Further research is needed to determine if users are aware of that alignment, which might indicate the politicization of lifestyle preferences. The findings also suggest an under-recognized way social media can promote polarization, not through political discourse or argument, but simply in how users present cultural and lifestyle preferences on those platforms.
Machine learning assisted exploration of the influential parameters on the PLGA nanoparticles
Authors: Rezvantalab Sima , Mihandoost Sara , Rezaiee Masoumeh
Published: January 2024

Poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) are widely investigated as drug delivery systems. However, despite the numerous reviews and research papers discussing various physicochemical and technical properties that affect NP size and drug loading characteristics, predicting the influential features remains difficult. In the present study, we employed four different machine learning (ML) techniques to create ML models using effective parameters related to NP size, encapsulation efficiency (E.E.%), and drug loading (D.L.%). These parameters were extracted from the different literature. Least Absolute Shrinkage and Selection Operator was used to investigate the input parameters and identify the most influential features (descriptors). Initially, ML models were trained and validated using tenfold validation methods, and subsequently, next their performances were evaluated and compared in terms of absolute error, mean absolute, error and R-square. After comparing the performance of different ML models, we decided to use support vector regression for predicting the size and E.E.% and random forest for predicting the D.L.% of PLGA-based NPs. Furthermore, we investigated the interactions between these target variables using ML methods and found that size and E.E.% are interrelated, while D.L.% shows no significant relationship with the other targets. Among these variables, E.E.% was identified as the most influential parameter affecting the NPs' size. Additionally, we found that certain physicochemical properties of PLGA, including molecular weight (Mw) and the lactide-to-glycolide (LA/GA) ratio, are the most determining features for E.E.% and D.L.% of the final NPs, respectively.
Conjunctival ultraviolet autofluorescence as a biomarker of outdoor exposure in myopia: a systematic review and meta-analysis
Authors: Rodriguez Natali Gutierrez , Claici Aura Ortega , Ramos-Castaneda Jorge A. , González-Zamora Jorge , Bilbao-Malavé Valentina , de la Puente Miriam , Fernandez-Robredo Patricia , Garzón-Parra Sandra Johanna , Garza-Leon Manuel , Recalde Sergio
Published: January 2024

Outdoor exposure is considered the primary modifiable risk factor in preventing the development of myopia. This effect is thought to be attributed to the light-induced synthesis and release of dopamine in the retina. However, until recent years, there was no objective quantifiable method available to measure the association between time spent outdoors and myopia. It is only recently that the conjunctival ultraviolet autofluorescence (CUVAF) area, serving as a biomarker for sun exposure, has begun to be utilized in numerous studies. To provide a comprehensive summary of the relevant evidence pertaining to the association between the CUVAF area and myopia across different geographic regions and age groups, a systematic review and meta-analysis were conducted. The search encompassed multiple databases, including MEDLINE, SCIENCE DIRECT, GOOGLE SCHOLAR, WEB OF SCIENCE, and SCOPUS, and utilized specific search terms such as "conjunctival ultraviolet autofluorescence", "CUVAF", "UVAF", "objective marker of ocular sun exposure", "myopia", "degenerative myopia", and "high myopia". The bibliographic research included papers published between the years 2006 and 2022. A total of 4051 records were initially identified, and after duplicates were removed, 49 articles underwent full-text review. Nine articles were included in the systematic review. These studies covered myopia and outdoor exposure across different regions (Australia, Europe and India) with a total population of 3615 individuals. They found that myopes generally had smaller CUVAF areas compared to non-myopes. The meta-analysis confirmed this, revealing statistically smaller CUVAF areas in myopic patients, with a mean difference of − 3.30 mm2 (95% CI − 5.53; − 1.06). Additionally, some studies showed a positive correlation between more outdoor exposure and larger CUVAF areas. In terms of outdoor exposure time, myopic patients reported less time outdoors than non-myopic individuals, with a mean difference of − 3.38 h/week (95% CI − 4.66; − 2.09). Overall, these findings highlight the connection between outdoor exposure, CUVAF area and myopia, with regional variations playing a significant role. The results of this meta-analysis validate CUVAF as a quantitative method to objectively measure outdoor exposure in relation with myopia development.