bluuebunny/crossref_metadata_2025 huggingface dataset:
Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
Authors: Romeo Maria Anele , Gilardini Montani Maria Saveria , Santarelli Roberta , Benedetti Rossella , Arena Andrea , Cirone Mara
Published: August 2023

PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it.
Skill heterogeneity and market labour income inequality
Authors: Medrano-Adán Luis , Salas-Fumás Vicente , Sanchez-Asin Javier
Published: August 2023

Occupational choice models predict that, ceteris paribus, countries with higher dispersion of skill will have higher market labour income inequality. However, an extended conclusion from empirical research is that cross-country variations in dispersion of skill explain little of the variation in income inequality. This paper identifies factors related to production and organization technologies that moderate the relationship between dispersion of skill and dispersion of income in occupational choice equilibrium outcomes and that, if not properly accounted for, can bias the results of the empirical studies that explain dispersion of income as a function of dispersion of skill. In particular, comparing equilibrium outcomes from occupational choices in economies that differ in the distribution of skill and in the efficiency of supervision hierarchies, the paper can explain why the US and Sweden have similar labour productivity, but income inequality is higher in the US than in Sweden, and why productivity is lower and income inequality is higher in Spain than in Sweden.
Chemically induced bacterial ghosts: a novel approach for advancing biomedical applications
Authors: Park Shin-Young
Published: August 2023

Background

Bacterial ghosts (BGs) are empty cell envelopes derived from bacteria, making them safe and non-replicative, and BGs have shown great potential as a vaccine platform. Specifically, chemically induced BGs are generated by selectively removing the cytoplasmic content of bacterial cells while preserving the structural integrity of the cell envelope.

Objective

Generally, BGs are genetically engineered, but this is limited to Gram-negative bacteria. However, the utilization of chemically induced BGs can be extended to Gram-positive bacteria, resulting in empty bacterial envelopes that hold potential as a platform for drug delivery.

Results

Chemically induced BGs offer several advantages, including improved safety profile and immunogenicity, and efficient antigen presentation. Preclinical studies have yielded promising results, exhibiting enhanced immune responses and protection against diverse pathogens.

Conclusion

Chemically induced BGs represent a novel and promising approach for vaccine development, holding the potential for advancing disease prevention and public health.

Purpose of review

In this review, we discuss key aspects of chemically induced BGs, including their production principles, mechanisms of formation, characterization techniques, immunogenicity, and medical applications. We also discuss the challenges and direction of future research for optimizing production methods for chemically induced BGs, evaluating long-term safety, and undertaking clinical trials to assess their efficacy.
Design, optimization, and in vivo evaluation of invasome-mediated candesartan for the control of diabetes-associated atherosclerosis
Authors: Fouad Amr Gamal , Ali Mohammed R. A. , Naguib Demiana M. , Farouk Hanan O. , Zanaty Mohamed I. , El-Ela Fatma I. Abo
Published: August 2023

Atherosclerosis is an inflammatory disease characterized by the accumulation of arterial plaque. Diabetes mellitus stands out as a major risk factor for atherosclerosis. Candesartan is a potent angiotensin II receptor antagonist that enhances arterial blood flow and reduces insulin resistance. However, oral candesartan has limited activity because of its low bioavailability, water solubility, hepatic first-pass degradation, and efficacy. The current study aims to develop nasal candesartan-loaded invasome (CLI) drops to improve candesartan’s permeation, release, and bioavailability as a potential treatment for diabetes-associated atherosclerosis. Design expert software was used to prepare various CLI formulations to determine the impact of the concentrations of ethanol, cineole, and phospholipid. The desirability index was used to estimate the optimized formulation composition to maximize entrapment efficiency and minimize vesicle size. The optimized formulation had a 1% ethanol concentration, a 1.5% cineole concentration, and a 2.32% phospholipid concentration. The selected optimized formulation was then tested in a rat model of diabetes and atherosclerosis to evaluate its activity. The results showed that nasal CLI drops significantly raised serum HDL levels by a ratio of 1.42 and lowered serum glucose, cholesterol, triglycerides, LDL, and VLDL levels by 69.70%, 72.22%, 36.52%, 58.0%, and 65.31%, respectively, compared with diabetic atherosclerotic rats, throwing an insight on the potential for promising anti-diabetic and anti-atherosclerotic activities. Additionally, atherosclerotic lesions were improved in rats treated with CLI, as shown in histopathology. In conclusion, the results of this investigation showed that treatment with nasal CSN-loaded invasome formulation drops prevented the initiation and progression of diabetes-associated atherosclerosis.

Graphical Abstract
The adjoint of an operator on a Banach space
Authors: García-Pacheco Francisco Javier
Published: August 2023

Self-adjoint operators in smooth Banach spaces have been already defined in recent works. Here, we extend the concept of adjoint of an operator to the scope of (non-necessarily Hilbert) Banach spaces, obtaining in particular the notion of self-adjoint operator in the non-smooth case. As a consequence, we define the probability density operator on Banach spaces and verify most of its well-known properties.
Congenital coenzyme Q5-linked pathology: causal genetic association, core phenotype, and molecular mechanism
Authors: Dawidziuk Mateusz , Podwysocka Aleksandra , Jurek Marta , Obersztyn Ewa , Bekiesinska-Figatowska Monika , Goszczanska-Ciuchta Alicja , Bukowska-Olech Ewelina , Rygiel Agnieszka Magdalena , Guilbride Dorothy Lys , Wiszniewski Wojciech , Gawlinski Pawel
Published: August 2023

Coenzyme Q5 (COQ5), a C-methyltransferase, modifies coenzyme Q10 (COQ10) during biosynthesis and interacts with polyA-tail regulating zinc-finger protein ZC3H14 in neural development. Here, we present a fifth patient (a third family) worldwide with neurodevelopmental and physiological symptoms including COQ10 deficiency. Our patient harbors one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. The patient’s mRNA profile reveals multiple COQ5 splice-variants. Subsequently, we comprehensively described patient’s clinical features as compared to phenotype and symptoms of other known congenital coenzyme Q5-linked cases. A core spectrum of COQ5-associated symptoms includes reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays. Our patient additionally displays dysmorphia, microcephaly, and regressive social faculties. These results formally establish causal association of biallelic COQ5 mutation with pathology, outline a core COQ5-linked phenotype, and identify mRNA mis-splicing as the molecular mechanism underlying all COQ5 variant-linked pathology to date.
Home ranges and movement patterns of wild boars (Sus scrofa) at the northern edge of the species’ distribution range
Authors: Miettinen E. , Melin M. , Holmala K. , Meller A. , Väänänen V.-M. , Huitu O. , Kunnasranta M.
Published: August 2023

In Finland, the wild boar (Sus scrofa L.) lives on the northernmost edge of the species’ distribution range, and the population mainly originates from individuals immigrating from Russia. Most of the current population lives in the southeastern part of the country, and the wild boar is steadily expanding further. To develop effective risk and population management in novel northern wild boar regions, detailed information about the species’ local ecology is required. To estimate wild boar movement patterns, 17 adult wild boars were monitored using GPS collars from May 2020 to September 2022 in the core region of the current distribution. The average total home ranges of wild boars (87.1 ± 17 km2 MCP, 33 ± 5.5 SE km2 95% KDE) were larger compared with studies from southern latitudes. The length of nocturnal activity times varied seasonally. All studied individuals at the border zone (N = 15) showed continuous transboundary movements, with home range core areas located mainly on the Russian side. Wild boar locations were predominantly in the Russia border zone, especially resting sites during the daytime. Most locations in Finland were from night-time feeding excursions. Our study shows that, although home ranges are large, adult wild boars are relatively sedentary also in northern latitudes. However, the movement capacity of the species enables the transboundary spread of diseases such as African swine fever. Our results provide information for risk management and emphasize the importance of transboundary collaboration in the monitoring and management of common wild boar populations.
The effectiveness of selected temporary testing protocols for gestational diabetes during the COVID-19 pandemic
Authors: Kania Michał , Wilk Magdalena , Cyganek Katarzyna , Szopa Magdalena
Published: August 2023

Objective

During the COVID-19 pandemic, the screening approach to the diagnosis of gestational diabetes mellitus (GDM) was subject to emergency simplifications. We aimed at assessing the effectiveness of two of these temporary pandemic protocols—namely the Australian and UK, and to examine the insights they gave into the effectiveness of the more standard WHO-outlined GDM diagnosis protocol.

Methods

We performed a retrospective analysis of 432 GDM patients attending the outpatient clinic at the University Hospital of Cracow, Poland throughout 2020.

Results

When applying the UK criteria, 272 (63.0%) of 432 GDM cases would be missed. Women with missed-GDM by UK criteria were slightly older, had lower BMI, and had lower use of insulin. The frequency of child perinatal complications was lower in the missed GDM group (7.6% vs. 18.9%, p = 0.042) when compared to the non-missed cases group. When applying the Australian criteria, 86 of 432 (19.9%) GDM cases would be missed. Women with missed-GDM by the Australian criteria had lower BMI and less commonly used insulin than the women not missed. There were no differences in the frequency of child and maternal complications.

Conclusions

Modifications proposed from the UK and Australia resulted in varying decreases and delays in GDM diagnoses, but with no apparent harm to mothers and offspring. More studies are required to investigate the impact of the simplification of GDM diagnosis on pregnancy outcomes.
Video Interventions for Reducing Health Inequity in Cancer Screening Programmes: a Systematic Review
Authors: Richardson-Parry Afua , Silva Mitchell , Valderas Jose Maria , Donde Shaantanu , Woodruff Seth , van Vugt Joris
Published: August 2023

Background

Health equity can lead to disparities in cancer screening, treatment, and mortality. This systematic review aims to identify and describe interventions that used video or DVD formats to reduce health inequity in cancer screening and review the effectiveness of such interventions in increasing screening rates compared to usual care conditions.

Methods

We searched PubMed, Web of Science, Embase, and Cochrane databases for randomized control trials (RCTs) published until 18/01/2023 that compared intervention versus usual care control groups, with the percentage of cancer screening uptake during follow-up as an outcome. The risk of Bias was assessed with the Cochrane Collaboration tool.

Results

After screening 4201 abstracts, 192 full texts were assessed for eligibility and 18 were included that focused on colorectal (n = 9), cervical (n = 5), breast (n = 5), and prostate (n = 1) cancer screening. All were based in the USA except one and most focused on ethnicity/race, while some included low-income populations. Most of the video interventions used to increase cervical cancer screening reported positive results. Studies aimed at increasing mammography uptake were mostly effective only in specific groups of participants, such as low-income or less-educated African American women. Results for colorectal cancer screening were conflicting. Videos that were culturally tailored or used emotive format were generally more effective than information-only videos.

Conclusions

Video interventions to increase cancer screening among populations with low screening uptake show some positive effects, though results are mixed. Interventions that use individual and cultural tailoring of the educational material should be further developed and investigated outside of the USA.
Effect of zirconium oxide nanofiber on the strength and chloride ion penetration coefficient of concrete
Authors: Zarea Yaser , Parhoodeh Saeed , Shahryari Leila , Karbakhsh Ali
Published: August 2023

In this study, zirconium oxide nanofiber with a mean diameter of 100 nm was added to concrete at various concentrations as a cement replacement. Various tests, including compressive strength, splitting tensile strength, flexural strength, and electrical resistance tests, as well as a rapid chloride penetration test, were performed on specimens containing zirconium oxide nanofibers for the concrete assessment, and the results were compared to those obtained from control specimens that did not contain nanofibers. The results showed that adding zirconium oxide nanofibers at 135 gr/m3 of concrete yielded a 28-day compressive strength equal to 44.62 MPa, which exhibits a 20.40% increase in strength with respect to the specimen that lacked nanofibers. The flexural strength and splitting tensile strength tests at 28 days of age and in the presence of 135 gr/m3 mentioned nanofibers were increased by 22.28 and 33.47%, respectively, in comparison to the control specimens. Moreover, revealed that at 28 days of age, in the specimens containing 270 gr/m3 zirconium oxide nanofibers, the migration coefficient of chloride ion was reduced by 29.86%, and its electrical resistance was increased by 68.33%. These findings highlight the potential of nanofibers as a promising solution for enhancing the strength and performance of concrete structures.
Sepsis-Associated Acute Kidney Injury
Authors: Wang Dong , Sun Tongwen , Liu Zhangsuo
Published: August 2023

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The kidneys are one of the first organs to be injured in sepsis. About two-thirds of patients with septic shock develop acute kidney injury, with a six- to eightfold increase in mortality. Growing evidences elucidate pathophysiological mechanisms, biomarkers, and response to therapy of sepsis-associated acute kidney injury (S-AKI). However, there is still a lack of effective and specific interventions for the treatment of S-AKI. This review summarizes the relevant evidence and provides an overview of the current understanding of S-AKI, focusing on pathophysiology, diagnosis, biomarkers, and therapeutic approaches.
Long‐Term Variability in Pliocene North Pacific Ocean Export Production and Its Implications for Ocean Circulation in a Warmer World
Authors: Abell Jordan T. , Winckler Gisela
Published: August 2023

Unlike in the high‐latitude North Atlantic, no deep water is formed in the modern subarctic North Pacific. It has previously been suggested that during climate states different from today, this dichotomy did not endure, and the formation of North Pacific Deepwater (NPDW) occurred in the subarctic North Pacific, which supported an active Pacific meridional overturning circulation (PMOC). Here we provide new records of productivity and sedimentary redox conditions from the central subarctic North Pacific spanning the late Miocene to early Pleistocene. These reconstructions indicate greater‐than‐modern and temporally varying North Pacific export production across the interval of ∼2.7–6 Ma. Our time series, combined with previously published data sets and model output for Pliocene North Pacific Ocean dynamics, support the presence of an active PMOC during the Pliocene, and suggest that the characteristics of NPDW formation varied during this warmer interval of Earth's history. This finding of elevated export production at a time of deep water formation presents a conundrum when considering Quaternary North Pacific Ocean dynamics, where subarctic North Pacific productivity declines during intervals when enhanced overturning is posited to occur. We evaluate our data considering the caveats of both (i.e., Pliocene and Quaternary North Pacific circulation) hypotheses, as well as additional mechanisms unrelated to ocean circulation. Because the Pliocene is a possible analogue for near‐future climate, our results and analyses have important ramifications for our understanding of regional and global climate in the coming decades as the planet continues to warm.
A Numerical Study of Dam‐Break Driven Swash and Beach Groundwater Interactions
Authors: Delisle Marie‐Pierre C. , Kim Yeulwoo , Gallien Timu W.
Published: August 2023

The dynamic interaction between swash and beach groundwater is fundamental to understanding wave runup and sediment transport processes. A numerical model that simultaneously resolves free surface and porous media flow for a variably saturated subsurface is presented. The novel numerical model, SedOlaFlow, is developed by merging the existing two‐phase, Eulerian sediment transport model, SedWaveFoam, with the surface wave solver, olaFlow. SedOlaFlow is validated with large wave flume surface and subsurface data for dam‐break driven swash over permeable gravel and sand beaches. Sediment size significantly impacts the swash‐groundwater relationship through infiltration/exfiltration and subsurface processes which modulate runup. Model results demonstrate that vertical infiltration into the upper unsaturated beach leads to a delayed groundwater table response to swash in the sand beach. Pressure fluctuations in the sand beach are not directly indicative of the swash depth or groundwater table and exfiltration may occur even when the swash depth is non‐zero. Groundwater circulation induced by a single swash event is non‐uniform and highly dynamic in the variably saturated vadose zone. Elevated ambient groundwater levels generally increase swash extent and duration. These findings establish the existence of a bi‐directional relationship between swash and groundwater flows and have significant implications on the effects of sea level rise on coastal flooding.
Improving CINRAD Radar QPE Through GPM‐DPR Reflectivity Bias Correction
Authors: Zhu Ziwei , Qi Youcun , Li Donghuan
Published: August 2023

Reflectivity bias of ground‐based weather radar (GR) is a common error source that can lead to biases in quantitative precipitation estimation (QPE). In this study, the Dual‐frequency Precipitation Radar onboard the Global Precipitation Measurement Mission Core Observatory (GPM‐DPR) is used to correct GR reflectivity bias. The reflectivity bias correction comprehensively considers variations in GR‐DPR reflectivity difference associated with radar frequency difference, data matching approach, precipitation type, GR orographic beam blockage, attenuation, and sample size. The criteria to perform a robust GR‐DPR comparison are presented. Disdrometer validation, based on eight typical rain events from April to August 2019, demonstrates that GPM‐DPR can effectively reduce GR reflectivity bias to ±1 dB. For the period from June to August 2021, the reflectivity correction method is applied to 17 operational GRs. The multiradar QPE shows a significant increase in correlation coefficient (from 0.62 to 0.71), and decreases in relative mean bias (from −0.28 to −0.19) and root mean square error (from 3.96 to 3.54 mm) compared to rain gauges. These results confirm that GPM‐DPR can effectively correct the reflectivity biases of a GR network and improve multiradar QPE accuracy and consistency.
Making a Superbolt: Reconciling Observations of the Optically Brightest Lightning on Earth From Different Satellites
Authors: Peterson Michael
Published: August 2023

We previously documented geographic distributions of the optically brightest lightning on Earth—known as “superbolts”—using two space‐based instruments: the photodiode detector (PDD) on the Fast On‐orbit Recording of Transient Events (FORTE) satellite and the Geostationary Lightning Mapper (GLM) on NOAA's Geostationary Operational Environmental Satellites. In this study, we further examine the superbolts identified by the PDD and GLM to reconcile the differences between their geographic distributions. We find that both the physical extent of the parent flash and the development speed of its leaders are important for making a superbolt. The oceanic PDD superbolts tend to occur early in flashes that rapidly expand laterally into long horizontal “megaflashes.” The top GLM superbolts occur over land at later times in particularly large megaflashes. These land‐based flashes grow more slowly until they extend over multiple hundreds of kilometers. The FORTE PDD missed these delayed superbolts due to limitations in its triggering. Coincident Tropical Rainfall Measuring Mission measurements show that the warm season megaflash superbolts detected by Lightning Imaging Sensor/GLM and wintertime oceanic superbolts observed by the PDD occur in otherwise similar thunderstorm environments. Both are marked by: low storm heights (<10 km), widespread precipitation near the surface, small infrared brightness temperature gradients, and low flash rates. We suggest that the vertically compact, stratiform nature of these clouds provides favorable conditions for superbolt production.
Role of Horizontal Heat Advection in Arctic Surface Warming During Early Spring
Authors: Dai Haijin
Published: August 2023

Reanalysis data and numerical model are employed to uncover the mechanisms of spring (March–April) Arctic surface warming. Different from other seasons, little additional solar radiation absorption or seasonal heat storage release contributes to Arctic surface warming in spring. Both observation and numerical results suggest that horizontal heat advection dominates Arctic surface air warming. However, horizontal advection originates from lower latitudes instead of local energy redistribution as in other seasons. Furthermore, Arctic warming weakens the meridional potential vorticity gradient, which strengthens the synoptic atmospheric blocking event. As a result, more warm (cold) air is transported to higher (lower) latitudes along the edge of high pressure, which is an accumulation of atmospheric blocking events. The results suggest that anomalous meridional heat transport plays more important roles in Arctic surface warming when the anomalous radiative forcing is weak. Without being absorbed by the ocean, additional available energy induces strong Arctic springtime surface warming.
Cold Springs Over Mid‐Latitude North America Induced by Tropical Atlantic Warming
Authors: Hou Yurong , Johnson Nathaniel C. , Chang Chueh‐Hsin , Sun Weijun , Man Kai , Miao Yujie , Li Xichen
Published: August 2023

In recent decades, severe cold winters and springs have frequently occurred over mid‐latitude North America, despite the anthropogenic global warming trend. In this study, we reveal a possible mechanism by investigating the teleconnection between tropical oceans and North America. Through observational analysis and numerical experiments, we reveal that an anomalous tropical Atlantic warming can trigger a cold spring over central‐western mid‐latitude North America. The tropical Atlantic warming intensifies regional deep atmospheric convection and generates a stationary Rossby wave train propagating poleward, forming an anomalous low pressure center over the mid‐latitude North Atlantic. This low‐level circulation adjustment further intensifies the cold advection and increases the cloud cover over central‐western North America, cooling the surface through cloud radiative feedback. The mechanisms revealed in this study may contribute to the improvement of predictability of cold springs over North America, and have broad implications for agriculture production, power supply, and public health.
Sensitivity of Pyrocumulus Convection to Tree Mortality During the 2020 Creek Fire in California
Authors: Lee Jungmin M. , Mirocha Jeffrey D. , Lareau Neil P. , Whitney Taylor , To Wing , Kochanski Adam , Lassman William
Published: August 2023

This study investigated the sensitivity of pyrocumulonimbus (PyroCb) induced by the California Creek fire of 2020 to the amount and type of surface fuels, within the WRF‐SFIRE modeling system. Satellite data were used to derive fire arrival times to constrain fire progression, and to augment the fuel characterization with better estimates of combustible vegetation accounting for tree mortality. Machine learning was employed to classify standing dead vegetation from aerial imagery, which was then added as a custom fuel class along with the standard Anderson fuel categories. Simulations using this new fuel class produced a larger and more vigorous PyroCb than the control run, however, still under‐predicted the cloud top. Additional augmentation of fuel mass to represent the accumulation of dead vegetation on the forest floor further improved the simulations, demonstrating the efficacy of representing both dead standing and fallen vegetation to produce more realistic PyroCb and smoke simulations.
Energy Transfer Between Mesoscale Eddies and Near‐Inertial Waves From Surface Drifter Observations
Authors: Liu Gengbin , Chen Zhiwu , Lu Huaihao , Liu Zhiyu , Zhang Qian , He Qingyou , He Yinghui , Xu Jiexin , Gong Yankun , Cai Shuqun
Published: August 2023

Hourly satellite‐tracked surface drifter data are utilized to study energy transfer from eddies to Near‐Inertial Waves (NIWs). Spatial velocity gradients are computed from two consecutive velocity estimates derived from the same drifter, providing variable spatial resolutions of O(1 km). The eddy‐to‐NIW energy transfer can be positive or negative, with the positive transfer (forward energy cascade) dominant. The global integrated energy transfer rate (ε) is 0.025 TW, with the anticyclonic eddy contribution dominant over the cyclonic eddy contribution. Given that the global near‐inertial wind work (W) is 0.2 TW, the eddy‐to‐NIW energy transfer efficiency (ε/W) is about 13%, which is one order of magnitude larger than that in low resolution simulations. This result may still underestimate the Eulerian energy transfer by a factor of 2. To our knowledge, this is the first time that this energy transfer is calculated from global drifter observations, providing a baseline for comparison in future studies.
Nutritional Status Regulates Bacteria‐Virus Interactions in the Northern South China Sea
Authors: Li Xiangfu , He Maoqiu , Shi Zhen , Xu Jie
Published: August 2023

Heterotrophic bacteria play a vital role in the marine carbon cycle and viruses are an important regulator of bacterial metabolism and community composition. It remains unclear about how bacteria‐virus interactions vary with environmental conditions in oceans. In this study, bacterial metabolic activity and community composition were examined in three treatments with different viral pressure (control, virus‐rich and virus‐reduced) through bioassay experiments at three stations with different environmental conditions in the shelf of the northern South China Sea. Our results showed that bacteria‐virus interactions varied with environmental conditions. Viral lysis mediated bacterial growth rate (BGR) and production by shaping bacterial community composition. Furthermore, the effect of viral lysis on bacterial growth rate and production was reduced in substrate‐rich waters compared to substrate‐low waters. However, the opposite pattern occurred for viral regulation on bacterial respiration and carbon demand, likely since viral lysis dramatically mitigated the maintenance respiration of bacteria. Consequently, viral lysis to greater extent mitigated bacterial carbon processing in substrate‐rich environments than in substrate‐low environments. Our findings provided new insights into bacteria‐virus interactions, and improved our understanding of the role microbial processes in carbon cycling in oceans.
Simulating Sea‐Ice Deformation in Viscous‐Plastic Sea‐Ice Models With CD‐Grids
Authors: Mehlmann C. , Capodaglio G. , Danilov S.
Published: August 2023

Linear kinematic features (LKFs) are found everywhere in the Arctic sea‐ice cover. They are strongly localized deformations often associated with the formation of leads and pressure ridges. In viscous‐plastic (VP) sea‐ice models, the simulation of LKFs depends on several factors such as the grid resolution, the numerical solver convergence, and the placement of the variables on the mesh. In this study, we compare two recently proposed discretization with a CD‐grid placement with respect to their ability to reproduce LKFs. The first (CD1) is based on a nonconforming finite element discretization, whereas the second (CD2) uses a conforming subgrid discretization. To analyze their resolution properties, we evaluate runs from different models (e.g., FESOM, MPAS) on a benchmark problem using quadrilateral, hexagonal and triangular meshes. Our findings show that the CD1 setup simulates more deformation structure than the CD2 setup. This highlights the importance of the type of spatial discretization for the simulation of LKFs. Due to the higher number of degrees of freedom, both CD‐grids resolve more LKFs than traditional A, B, and C‐grids at fixed mesh level. This is an advantage of the CD‐grid approach, as high spatial mesh resolution is needed in VP sea‐ice models to simulate LKFs.
A microfluidic biosensor for the diagnosis of chronic wasting disease
Authors: Muhsin Sura A. , Abdullah Amjed , kobashigawa Estela , Al-Amidie Muthana , Russell Sherri , Zhang Michael Z. , Zhang Shuping , Almasri Mahmoud
Published: August 2023

Cervids are affected by a neurologic disease that is always fatal to individuals and has population effects. This disease is called chronic wasting disease (CWD) and is caused by a misfolded prion protein. The disease is transmitted via contact with contaminated body fluids and tissue or exposure to the environment, such as drinking water or food. Current CWD diagnosis depends on ELISA screening of cervid lymph nodes and subsequent immunohistochemistry (IHC) confirmation of ELISA-positive results. The disease has proven to be difficult to control in part because of sensitivity and specificity issues with the current test regimen. We have investigated an accurate, rapid, and low-cost microfluidic microelectromechanical system (MEMS) biosensing device for the detection of CWD pathologic prions in retropharyngeal lymph nodes (RLNs), which is the current standard type of CWD diagnostic sample. The device consists of three novel regions for concentrating, trapping, and detecting the prion. The detection region includes an array of electrodes coated with a monoclonal antibody against pathologic prions. The experimental conditions were optimized using an engineered prion control antigen. Testing could be completed in less than 1 hour with high sensitivity and selectivity. The biosensor detected the engineered prion antigen at a 1:24 dilution, while ELISA detected the same antigen at a 1:8 dilution. The relative limit of detection (rLOD) of the biosensor was a 1:1000 dilution of a known strong positive RLN sample, whereas ELISA showed a rLOD of 1:100 dilution. Thus, the biosensor was 10 times more sensitive than ELISA, which is the currently approved CWD diagnostic test. The biosensor’s specificity and selectivity were confirmed using known negative RPLN samples, a negative control antibody (monoclonal antibody against bovine coronavirus BCV), and two negative control antigens (bluetongue virus and Epizootic hemorrhagic disease virus). The biosensor’s ability to detect pathogenic prions was verified by testing proteinase-digested positive RLN samples.
Journey towards a dental career: the career decision-making journey and perceived obstacles to studying dentistry identified by London's secondary school pupils and teachers
Authors: Niven Victoria , Scambler Sasha , Cabot Lyndon B. , Gallagher Jennifer E.
Published: August 2023

ObjectiveTo explore the career decision-making journey towards dentistry and identify possible challenges and supports in this process as perceived by academically able, science-minded, London school pupils and their careers teachers.

MethodsA mixed-methods study was conducted using a purposive sample of London schools. Focus groups (n = 13) with 91 pupils aged 14-18 years and a survey of career teachers (n = 12) were conducted at a range of school-types. A topic guide, informed by the literature and previous research, guided discussions. Ethical approval was obtained from King's College London Research Ethics Committee (BDM/10/11-17 and 14/15-40). School, teacher, parental and pupil written informed consent were obtained. Data were transcribed and analysed thematically using framework methodology.

ResultsFour distinct phases of the career decision-making journey were identified: 1) initiation of aspiration, with wider influences promoting medicine as a primary aspirational career option; 2) exposure to dentistry as a career, leading to recognition of dentistry as an alternative; 3) exploration of the career; and 4) the application process. Dentistry received little early consideration in this process. Greater representation of dental professionals within the school, access to work experience, and support in the student application process were identified as possible supports.

ConclusionsThe findings suggest a four-phase journey towards a dental career, which may be enhanced by engagement of dental professionals at each stage. This may be particularly helpful in widening participation from under-represented groups.
Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration
Authors: Liang Huaizhen , Luo Rongjin , Li Gaocai , Zhang Weifeng , Zhu Dingchao , Wu Di , Zhou Xingyu , Tong Bide , Wang Bingjin , Feng Xiaobo , Wang Kun , Song Yu , Yang Cao
Published: August 2023

Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3–9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention.
A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels
Authors: Liu Yichen , Bassetto Carlos A. Z. , Pinto Bernardo I. , Bezanilla Francisco
Published: August 2023

The hinged-lid model was long accepted as the canonical model for fast inactivation in Nav channels. It predicts that the hydrophobic IFM motif acts intracellularly as the gating particle that binds and occludes the pore during fast inactivation. However, the observation in recent high-resolution structures that the bound IFM motif is located far from the pore, contradicts this preconception. Here, we provide a mechanistic reinterpretation of fast inactivation based on structural analysis and ionic/gating current measurements. We demonstrate that in Nav1.4 the final inactivation gate is comprised of two hydrophobic rings at the bottom of S6 helices. These rings function in series and close downstream of IFM binding. Reducing the volume of the sidechain in both rings leads to a partially conductive, leaky inactivated state and decreases the selectivity for Na+ ion. Altogether, we present an alternative molecular framework to describe fast inactivation.
Sequence anticipation and spike-timing-dependent plasticity emerge from a predictive learning rule
Authors: Saponati Matteo , Vinck Martin
Published: August 2023

Intelligent behavior depends on the brain’s ability to anticipate future events. However, the learning rules that enable neurons to predict and fire ahead of sensory inputs remain largely unknown. We propose a plasticity rule based on predictive processing, where the neuron learns a low-rank model of the synaptic input dynamics in its membrane potential. Neurons thereby amplify those synapses that maximally predict other synaptic inputs based on their temporal relations, which provide a solution to an optimization problem that can be implemented at the single-neuron level using only local information. Consequently, neurons learn sequences over long timescales and shift their spikes towards the first inputs in a sequence. We show that this mechanism can explain the development of anticipatory signalling and recall in a recurrent network. Furthermore, we demonstrate that the learning rule gives rise to several experimentally observed STDP (spike-timing-dependent plasticity) mechanisms. These findings suggest prediction as a guiding principle to orchestrate learning and synaptic plasticity in single neurons.
Effects of drought and recovery on soil volatile organic compound fluxes in an experimental rainforest
Authors: Pugliese Giovanni , Ingrisch Johannes , Meredith Laura K. , Pfannerstill Eva Y. , Klüpfel Thomas , Meeran Kathiravan , Byron Joseph , Purser Gemma , Gil-Loaiza Juliana , van Haren Joost , Dontsova Katerina , Kreuzwieser Jürgen , Ladd S. Nemiah , Werner Christiane , Williams Jonathan
Published: August 2023

Drought can affect the capacity of soils to emit and consume biogenic volatile organic compounds (VOCs). Here we show the impact of prolonged drought followed by rewetting and recovery on soil VOC fluxes in an experimental rainforest. Under wet conditions the rainforest soil acts as a net VOC sink, in particular for isoprenoids, carbonyls and alcohols. The sink capacity progressively decreases during drought, and at soil moistures below ~19%, the soil becomes a source of several VOCs. Position specific 13C-pyruvate labeling experiments reveal that soil microbes are responsible for the emissions and that the VOC production is higher during drought. Soil rewetting induces a rapid and short abiotic emission peak of carbonyl compounds, and a slow and long biotic emission peak of sulfur-containing compounds. Results show that, the extended drought periods predicted for tropical rainforest regions will strongly affect soil VOC fluxes thereby impacting atmospheric chemistry and climate.
Spin-orbit driven superconducting proximity effects in Pt/Nb thin films
Authors: Flokstra Machiel , Stewart Rhea , Yim Chi-Ming , Trainer Christopher , Wahl Peter , Miller David , Satchell Nathan , Burnell Gavin , Luetkens Hubertus , Prokscha Thomas , Suter Andreas , Morenzoni Elvezio , Bobkova Irina V. , Bobkov Alexander M. , Lee Stephen
Published: August 2023

Manipulating the spin state of thin layers of superconducting material is a promising route to generate dissipationless spin currents in spintronic devices. Approaches typically focus on using thin ferromagnetic elements to perturb the spin state of the superconducting condensate to create spin-triplet correlations. We have investigated simple structures that generate spin-triplet correlations without using ferromagnetic elements. Scanning tunneling spectroscopy and muon-spin rotation are used to probe the local electronic and magnetic properties of our hybrid structures, demonstrating a paramagnetic contribution to the magnetization that partially cancels the Meissner screening. This spin-orbit generated magnetization is shown to derive from the spin of the equal-spin pairs rather than from their orbital motion and is an important development in the field of superconducting spintronics.
An X-ray free-electron laser with a highly configurable undulator and integrated chicanes for tailored pulse properties
Authors: Prat Eduard , Al Haddad Andre , Arrell Christopher , Augustin Sven , Boll Marco , Bostedt Christoph , Calvi Marco , Cavalieri Adrian L. , Craievich Paolo , Dax Andreas , Dijkstal Philipp , Ferrari Eugenio , Follath Rolf , Ganter Romain , Geng Zheqiao , Hiller Nicole , Huppert Martin , Ischebeck Rasmus , Juranić Pavle , Kittel Christoph , Knopp Gregor , Malyzhenkov Alexander , Marcellini Fabio , Neppl Stefan , Reiche Sven , Sammut Nicholas , Schietinger Thomas , Schmidt Thomas , Schnorr Kirsten , Trisorio Alexandre , Vicario Carlo , Voulot Didier , Wang Guanglei , Weilbach Tobias
Published: August 2023

X-ray free-electron lasers (FELs) are state-of-the-art scientific tools capable to study matter on the scale of atomic processes. Since the initial operation of X-ray FELs more than a decade ago, several facilities with upgraded performance have been put in operation. Here we present the first lasing results of Athos, the soft X-ray FEL beamline of SwissFEL at the Paul Scherrer Institute in Switzerland. Athos features an undulator layout based on short APPLE-X modules providing full polarisation control, interleaved with small magnetic chicanes. This versatile configuration allows for many operational modes, giving control over many FEL properties. We show, for example, a 35% reduction of the required undulator length to achieve FEL saturation with respect to standard undulator configurations. We also demonstrate the generation of more powerful pulses than the ones obtained in typical undulators. Athos represents a fundamental step forward in the design of FEL facilities, creating opportunities in FEL-based sciences.
Direct visual observation of pedal motion-dependent flexibility of single covalent organic frameworks
Authors: Chi Hongbin , Liu Yang , Li Ziyi , Chen Wanxin , He Yi
Published: August 2023

Flexible covalent organic frameworks (COFs) have been studied for applications containing sorption, selective separation, and catalysis. How to correlate the microscopic structure with flexibility in COFs is a great challenge. Herein, we visually track the flexible deformation behaviors of single COF-300 and COF-300-AR particles in response to solvent vapour guests with dark-field microscopy (DFM) in an in operando manner. COF-300-AR with freely-rotating C-N single bonds are synthesized by the reduction of imine-based COF-300 consisting of rigid C=N double bonds without changing topological structure and crystallinity. Unexpectedly, we observe that the flexible deformation of COF-300 is extremely higher than that of COF-300-AR despite it bears many C-N single bonds, clearly illustrating the apparent flexibility decrease of COF-300 after reduction. The high spatiotemporal resolution of DFM enables the finding of inter-particle variations of the flexibility among COF-300 crystals. Experimental characterizations by variable-temperature X-ray diffraction and infrared spectroscopy as well as theoretical calculations demonstrate that the flexible deformation of COF-300 is ascribed to the pedal motion around rigid C=N double bonds. These observations provide new insights into COF flexibility.
Allosteric control of olefin isomerization kinetics via remote metal binding and its mechanochemical analysis
Authors: Yu Yichen , O’Neill Robert T. , Boulatov Roman , Widenhoefer Ross A. , Craig Stephen L.
Published: August 2023

Allosteric control of reaction thermodynamics is well understood, but the mechanisms by which changes in local geometries of receptor sites lower activation reaction barriers in electronically uncoupled, remote reaction moieties remain relatively unexplored. Here we report a molecular scaffold in which the rate of thermal E-to-Z isomerization of an alkene increases by a factor of as much as 104 in response to fast binding of a metal ion to a remote receptor site. A mechanochemical model of the olefin coupled to a compressive harmonic spring reproduces the observed acceleration quantitatively, adding the studied isomerization to the very few reactions demonstrated to be sensitive to extrinsic compressive force. The work validates experimentally the generalization of mechanochemical kinetics to compressive loads and demonstrates that the formalism of force-coupled reactivity offers a productive framework for the quantitative analysis of the molecular basis of allosteric control of reaction kinetics. Important differences in the effects of compressive vs. tensile force on the kinetic stabilities of molecules are discussed.
MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping
Authors: Filipescu Dan , Carcamo Saul , Agarwal Aman , Tung Navpreet , Humblin Étienne , Goldberg Matthew S. , Vyas Nikki S. , Beaumont Kristin G. , Demircioglu Deniz , Sridhar Subhasree , Ghiraldini Flavia G. , Capparelli Claudia , Aplin Andrew E. , Salmon Hélène , Sebra Robert , Kamphorst Alice O. , Merad Miriam , Hasson Dan , Bernstein Emily
Published: August 2023

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.