bluuebunny/crossref_metadata_2025 huggingface dataset:
Gaussian Process Regression‐Based Bayesian Optimisation (G‐BO) of Model Parameters—A WRF Model Case Study of Southeast Australia Heat Extremes
Authors: Reddy P. Jyoteeshkumar , Chinta Sandeep , Baki Harish , Matear Richard , Taylor John
Published: September 2024

In Numerical Weather Prediction (NWP) models, such as the Weather Research and Forecasting (WRF) model, parameter uncertainty in physics parameterization schemes significantly impacts model output. Our study adopts a Bayesian probabilistic approach, building on prior research that identified temperature (T) and relative humidity (Rh) as sensitive to three key WRF parameters during southeast Australia's extreme heat events. Using Gaussian process regression‐based Bayesian Optimisation (G‐BO), we accurately estimated the optimal distributions for these parameters. Results show that the default values are outside their corresponding optimal distribution bounds for two of the three parameters, suggesting the need to reconsider these default values. Additionally, the robustness of the optimal parameter distributions is validated by their application to an independent extreme heat event, not included in the optimisation process. In this test, the optimized parameters substantially improved the simulation of T and Rh, highlighting their effectiveness in enhancing simulation accuracy during extreme heat conditions.
Strong Lg‐Wave Attenuation Reveals Quarter‐Toroidal Crustal Melting Around the Yakutat Terrane in South‐Central Alaska
Authors: Yang Geng , Zhao Lian‐Feng , Xie Xiao‐Bi , He Xi , Zhang Lei , Yao Zhen‐Xing
Published: September 2024

South‐central Alaska features a history of massive volcanic activity. How the Denali volcanic gap (DVG) formed and why the Wrangell volcanoes are clustered remain vigorously debated. Investigating the crustal thermal structure can be crucial for understanding subsurface magmatic activity. We present a high‐resolution broadband Lg‐wave attenuation model to constrain crustal thermal anomalies beneath Alaska. Strong Lg attenuation is observed beneath the volcanoes in south‐central Alaska, indicating thermal anomalies and possible melting in the crust. In contrast, the central Yakutat terrane (YT) and DVG are characterized by weak Lg attenuation, suggesting the existence of a cool crust that prevents hot mantle materials from invading the crust. This cool crust is likely the reason for the DVG. Quarter‐toroidal crustal melting with strong attenuation is revealed around the YT. This curved zone of crustal melting, possibly driven by toroidal mantle flow, weakly connects the Wrangell and Buzzard Creek‐Jumbo Dome magmatic chambers.
Gene-environment correlation: the role of family environment in academic development
Authors: Zhou Quan , Gidziela Agnieszka , Allegrini Andrea G. , Cheesman Rosa , Wertz Jasmin , Maxwell Jessye , Plomin Robert , Rimfeld Kaili , Malanchini Margherita
Published: September 2024

Academic achievement is partly heritable and highly polygenic. However, genetic effects on academic achievement are not independent of environmental processes. We investigated whether aspects of the family environment mediated genetic effects on academic achievement across development. Our sample included 5151 children who participated in the Twins Early Development Study, as well as their parents and teachers. Data on academic achievement and family environments (parenting, home environments, and geocoded indices of neighbourhood characteristics) were available at ages 7, 9, 12 and 16. We computed educational attainment polygenic scores (PGS) and further separated genetic effects into cognitive and noncognitive PGS. Three core findings emerged. First, aspects of the family environment, but not the wider neighbourhood context, consistently mediated the PGS effects on achievement across development—accounting for up to 34.3% of the total effect. Family characteristics mattered beyond socio-economic status. Second, family environments were more robustly linked to noncognitive PGS effects on academic achievement than cognitive PGS effects. Third, when we investigated whether environmental mediation effects could also be observed when considering differences between siblings, adjusting for family fixed effects, we found that environmental mediation was nearly exclusively observed between families. This is consistent with the proposition that family environmental contexts contribute to academic development via passive gene-environment correlation processes or genetic nurture. Our results show how parents tend to shape environments that foster their children’s academic development partly based on their own genetic disposition, particularly towards noncognitive skills, rather than responding to each child’s genetic disposition.
GLP-1 receptor agonist exenatide uncouples food intake from hedonic and anticipatory regulation in non-human primates: insights from an operant meal schedule paradigm
Authors: Knakker Balázs , Inkeller Judit , Kovács Péter , Lendvai Balázs , Hernádi István
Published: September 2024

Glucagon-like peptide 1 (GLP-1), a neuroendocrine signal of energy balance and satiety, has a major role in regulating food intake behaviour. Here we investigated the effects of the GLP-1 agonist exenatide on palatability-driven feeding regulation in adult male rhesus macaques (n = 5) using a novel operant food intake paradigm with four meal schedule conditions where two types of pellets with different palatability values were offered as meal in all combinations in two consecutive daily feeding sessions (S1 and S2). In control conditions, a strong, palatability-driven anticipatory effect was found in S1, followed by a complementary positive contrast effect in S2. After acute subcutaneous treatment with 1 µg/kg dose of exenatide 1 h before S1, food intake decreased to the same very low level in all meal schedule conditions in S1, completely erasing the previously observed anticipatory effect. Conversely, exenatide induced hypoglycaemia in an anticipatory meal schedule dependent pattern. Interestingly, the previously observed positive contrast effect was spared in S2, with a weaker residual effect specifically on the consumption of the more palatable pellet type. To conclude, the food intake reducing effects of exenatide may temporally evolve from strong anorectic to weak anhedonic modulations, where hedonic experience and anticipation during the early anorectic phase is conserved but uncoupled from food intake behaviour.
Psychiatric disorders and comorbidity in women with Turner Syndrome: a retrospective national cohort study
Authors: Thunström Sofia , Wide Ulla , Landin-Wilhelmsen Kerstin , Berntorp Kerstin , Bryman Inger , Krantz Emily , Wahlberg Jeanette , Ekman Bertil , Isakson Magnus , Karlsson Anders , Bergström Ingrid , Naessén Sabine
Published: September 2024

Turner syndrome (TS) is a genetic condition characterized by partial or complete monosomy X. A reduced life expectancy has been shown in TS, depending on an increased risk of aortic dissection, and ischemic heart disease. Studies covering the occurrence of psychiatric conditions are sparse within TS. Several case reports describe concomitant TS and neuropsychiatric abnormalities that may represent a pathogenetic link to genetics, as well as feature correlates of TS. The aim of this study was to determine the presence, and the frequency of psychiatric diagnosis in women with TS in a Swedish cohort followed during 25 years’ time. Statistics from the entire female population in Sweden of corresponding age was used as reference. Data were retrieved from clinical examinations and validated from the National Board of Health and Welfare registries for women with TS (n = 487), aged 16 to 84 years, with respect to mental health disorders. The most common diagnoses in TS were mood and anxiety disorders. There was no increase in psychiatric diagnosis within the group with time, nor correlation to specific karyotype or somatic comorbidity as congenital heart disease and hypothyroidism, hormonal treatment, or childbirth. In addition, the frequency of psychiatric diagnosis in TS was lower than in the population-based data. Further investigations are needed in the view of the fact that women with Turner syndrome should not be burdened with more severe diagnoses.
Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants
Authors: Vizeli Patrick , Studerus Erich , Holze Friederike , Schmid Yasmin , Dolder Patrick C. , Ley Laura , Straumann Isabelle , Becker Anna M. , Müller Felix , Arikci Denis , Liechti Matthias E.
Published: September 2024

The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25–200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as “Well-Being”, “Emotional Excitability”, and “Anxiety” were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait “Openness to Experiences” was positively correlated with elevated ratings in “Oceanic Boundlessness” and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with “Anxious Ego Dissolution”. Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience.
Comorbidity in patients with cancer treated at The Christie
Authors: Abravan Azadeh , Faivre-Finn Corinne , Gomes Fabio , van Herk Marcel , Price Gareth
Published: September 2024

Background

Comorbidities have been shown to impact the presentation and treatment of patients with cancers. This study investigates the prevalence and patterns of comorbidity in a pan-cancer cohort of patients treated at a large UK specialist cancer center over a 9-year period.

Methods

A retrospective review of 77,149 patients from 01/01/2014 to 15/12/2022 was conducted using the Adult Comorbidity Evaluation 27 score (ACE-27) to assess the burden of comorbidities across 12 organ systems and an overall comorbidity burden. Binary and multinomial logistic regressions were utilized to evaluate the relationships between comorbidity incidence and demographic and socio-economic factors.

Results

At the time of diagnosis, 59.7% of patients had at least one comorbidity, with the highest prevalence in lung cancer and the lowest in brain/CNS and endocrine gland cancers. Cardiovascular comorbidities were the most frequent. Comorbidity severity was higher in patients from more deprived areas. Age and performance status were associated with a higher incidence of all comorbidities examined. Patients with advanced stage had a lower risk of having a severe comorbidity burden.

Conclusion

Comorbidities are common across all cancers but are more prevalent in certain patient populations. Further research to understand the implications of comorbidities in cancer management is needed.
L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma
Authors: Zhang Zihe , Li Yongwen , Shi Ruifeng , Jia Chaoyi , Xu Songlin , Zhu Guangsheng , Cao Peijun , Huang Hua , Li Xuanguang , Zhang Hongbing , Liu Minghui , Chen Chen , Liu Hongyu , Kang Chunsheng , Chen Jun
Published: September 2024

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.
Renalase rs2296545 variant improve hypertension susceptibility by modifying binding affinity to catecholamines in obstructive sleep apnea
Authors: Shen Hangdong , Yang Jundong , Xue Wenjun , Wei Zhicheng , Li Lilin , Guan Jian , Li Xinyi , Wu Xiaolin
Published: September 2024

Obstructive sleep apnea (OSA), a condition often linked with hypertension, has an undefined relationship with renalase, a protein known for regulating blood pressure. This study aimed to investigate the relationship between serum renalase levels as well as renalase functional single nucleotide polymorphism (SNP) rs2296545 variant and hypertension in a Han Chinese OSA population. 126 subjects underwent serum renalase detection, with linear regression being performed to evaluate the relationship between serum renalase levels and OSA-related traits. Additional 4275 subjects were obtained rs2296545 genotype information by SNP microarray. And binary logistic regression was used to assess the effect of rs2296545 on hypertension risk. Molecular dynamics simulation and molecular docking were utilized to access the protein structures and the interplay between protein and catecholamines of wild-type and rs2296545 mutant renalase. The results showed that serum renalase levels were significantly higher in the severe OSA group. Further analysis showed renalase levels were positively correlated with blood pressure in the non-OSA group and negatively correlated in the severe OSA group. For rs2296545 polymorphism analysis, the hypertension risk significantly increased for the recessive model CC/GG + CG (OR = 1.211, 95% CI: 1.025–1.431) and the additive model CC/CG (OR = 1.223, 95% CI: 1.025–1.458) in the severe OSA. The rs2296545 polymorphism affected protein structure, and led to increase binding free energy, weakening interactions between renalase and catecholamines. In conclusion, serum renalase levels had independent association with blood pressure. And rs2296545 polymorphism may influence on susceptibility to hypertension by altering protein ability to bind to catecholamines, which might contribute to the intervention of hypertension in the OSA population.
Photochemical conversion of CO to C1 and C2 products mediated by porphyrin rhodium(II) metallo-radical complexes
Authors: Li Hongsen , Han Boao , Wang Rongyi , Li Wentao , Zhang Wentao , Fu Xuefeng , Fang Huayi , Ma Fuqiu , Wang Zikuan , Zhang Jiajing
Published: September 2024

Unimolecular reduction and bimolecular reductive coupling of carbon monoxide (CO) represent important ways to synthesize organic feedstocks. Reductive activation of CO through open-shell pathways, though rare, can help overcome the barriers of many traditional organometallic elementary reactions that are hard to achieve. Herein we successfully achieve the unimolecular reduction of CO to (TPP)RhCH2OSiR1R2R3 (TPP = 5,10,15,20-tetraphenylporphyrin), and the release of products CH3OSiR1R2R3, TEMPO-CH2OSiR1R2R3 and BrCH2OSiR1R2R3 in near-quantitative yield under visible light (420–780 nm), which involves radical formation from Rh-C bond homolysis. Bimolecular CO reductive coupling products, (TPP)RhCOCH2OSiR1R2R3, are then obtained via a radical mechanism. Subsequent treatment with n-propylamine, BrCCl3 or TEMPO under thermal or photochemical conditions afford small-molecule bimolecular reductive coupling products. To the best of our knowledge, homogeneous systems which reductively couple CO under photochemical conditions have not been reported before. Here, the use of an open-shell transition metal complex, that delivers more than one kind of small-molecule CO reductive coupling products bearing different functional groups, provides opportunities for useful CO reductive transformations.
12.1 terabit/second data center interconnects using O-band coherent transmission with QD-MLL frequency combs
Authors: Bernal Santiago , Dumont Mario , Berikaa Essam , St-Arnault Charles , Hu Yixiang , Castrejon Ramon Gutierrez , Li Weijia , Wei Zixian , Krueger Benjamin , Pittalà Fabio , Bowers John , Plant David V.
Published: September 2024

Most current Data Center Interconnects (DCI) use intensity modulation direct detection (IMDD) configurations due to their low complexity and cost. However, significant scaling challenges allow coherent solutions to become contenders in these short reach applications. We present an O-band coherent optical fiber transmission system based on Quantum Dot—Mode Locked Lasers (QD-MLLs) using two independent free-running comb lasers, one each for the carrier and the Local Oscillator (LO). Using a comb-to-comb configuration, we demonstrate a 10 km single mode fiber, O-band, coherent, heterodyne, 12.1 Tbps system operating at 0.47 Tbps/λ using 26 λs. We used fewer comb lines (26 λs), faster symbol rate (56 GBaud) and higher constellation cardinality (32 QAM) relative to the highest capacity C-band systems reported to date. Through design, analysis, and experimentation, we quantify the optimum comb line spacing for this use case. We compare potential configurations for increasing data center interconnect capacities whilst reducing power consumption, complexity, and cost.
Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain
Authors: Polyzos Aris A. , Cheong Ana , Yoo Jung Hyun , Blagec Lana , Toprani Sneh M. , Nagel Zachary D. , McMurray Cynthia T.
Published: September 2024

We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.
Spatial segregation of catalytic sites within Pd doped H-ZSM-5 for fatty acid hydrodeoxygenation to alkanes
Authors: Ding Shengzhe , Fernandez Ainaga Dario Luis , Hu Min , Qiu Boya , Khalid Ushna , D’Agostino Carmine , Ou Xiaoxia , Spencer Ben , Zhong Xiangli , Peng Yani , Hondow Nicole , Theodoropoulos Constantinos , Jiao Yilai , Parlett Christopher M. A. , Fan Xiaolei
Published: September 2024

Spatial control over features within multifunctional catalysts can unlock efficient one-pot cascade reactions, which are themselves a pathway to aviation biofuels via hydrodeoxygenation. A synthesis strategy that encompasses spatial orthogonality, i.e., one in which different catalytic species are deposited exclusively within discrete locations of a support architecture, is one solution that permits control over potential interactions between different sites and the cascade process. Here, we report a Pd doped hierarchical zeolite, in which Pd nanoparticles are selectively deposited within the mesopores, while acidity is retained solely within the micropores of ZSM-5. This spatial segregation facilitates hydrodeoxygenation while suppressing undesirable decarboxylation and decarbonation, yielding significant enhancements in activity (30.6 vs 3.6 moldodecane molPd−1 h−1) and selectivity (C12:C11 5.2 vs 1.9) relative to a conventionally prepared counterpart (via wet impregnation). Herein, multifunctional material design can realise efficient fatty acid hydrodeoxygenation, thus advancing the field and inspiring future developments in rationalised catalyst design.
Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins
Authors: Arrowsmith Tom J. , Xu Xibing , Xu Shangze , Usher Ben , Stokes Peter , Guest Megan , Bronowska Agnieszka K. , Genevaux Pierre , Blower Tim R.
Published: September 2024

Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.
The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation
Authors: Makar Agata N. , Boraman Alina , Mosen Peter , Simpson Joanne E. , Marques Jair , Michelberger Tim , Aitken Stuart , Wheeler Ann P. , Winter Dominic , von Kriegsheim Alex , Gammoh Noor
Published: September 2024

Autophagy is a finely orchestrated process required for the lysosomal degradation of cytosolic components. The final degradation step is essential for clearing autophagic cargo and recycling macromolecules. Using a CRISPR/Cas9-based screen, we identify RNAseK, a highly conserved transmembrane protein, as a regulator of autophagosome degradation. Analyses of RNAseK knockout cells reveal that, while autophagosome maturation is intact, cargo degradation is severely disrupted. Importantly, lysosomal protease activity and acidification remain intact in the absence of RNAseK suggesting a specificity to autolysosome degradation. Analyses of lysosome fractions show reduced levels of a subset of hydrolases in the absence of RNAseK. Of these, the knockdown of PLD3 leads to a defect in autophagosome clearance. Furthermore, the lysosomal fraction of RNAseK-depleted cells exhibits an accumulation of the ESCRT-III complex component, VPS4a, which is required for the lysosomal targeting of PLD3. Altogether, here we identify a lysosomal hydrolase delivery pathway required for efficient autolysosome degradation.
Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma
Authors: Liu Yang , Ye Shuang-Yan , He Shuai , Chi Dong-Mei , Wang Xiu-Zhi , Wen Yue-Feng , Ma Dong , Nie Run-Cong , Xiang Pu , Zhou You , Ruan Zhao-Hui , Peng Rou-Jun , Luo Chun-Ling , Wei Pan-Pan , Lin Guo-Wang , Zheng Jian , Cui Qian , Cai Mu-Yan , Yun Jing-Ping , Dong Junchao , Mai Hai-Qiang , Xia Xiaojun , Bei Jin-Xin
Published: September 2024

Tertiary lymphoid structures are immune cell aggregates linked with cancer outcomes, but their interactions with tumour cell aggregates are unclear. Using nasopharyngeal carcinoma as a model, here we analyse single-cell transcriptomes of 343,829 cells from 77 biopsy and blood samples and spatially-resolved transcriptomes of 31,316 spots from 15 tumours to decipher their components and interactions with tumour cell aggregates. We identify essential cell populations in tertiary lymphoid structure, including CXCL13+ cancer-associated fibroblasts, stem-like CXCL13+CD8+ T cells, and B and T follicular helper cells. Our study shows that germinal centre reaction matures plasma cells. These plasma cells intersperse with tumour cell aggregates, promoting apoptosis of EBV-related malignant cells and enhancing immunotherapy response. CXCL13+ cancer-associated fibroblasts promote B cell adhesion and antibody production, activating CXCL13+CD8+ T cells that become exhausted in tumour cell aggregates. Tertiary lymphoid structure-related cell signatures correlate with prognosis and PD-1 blockade response, offering insights for therapeutic strategies in cancers.
Kinetic ferromagnetism and topological magnons of the hole-doped Kitaev spin liquid
Authors: Jin Hui-Ke , Kadow Wilhelm , Knap Michael , Knolle Johannes
Published: September 2024

We study the effect of hole doping on the Kitaev spin liquid (KSL) and find that for ferromagnetic (FM) Kitaev exchange K the system is very susceptible to the formation of a FM spin polarization. Through density matrix renormalization group simulations on finite systems, we uncover that the introduction of a single hole, corresponding to ≈1% hole doping for the system size we consider, with a hopping strength of just t ~ 0.28K is enough to disrupt fractionalization and polarize the spins in the [001] direction due to an order-by-disorder mechanism. Taking into account a material relevant FM anisotropic exchange Γ drives the polarization towards the [111] direction via a transition into a topological FM state with chiral magnon excitations. We develop a parton mean-field theory incorporating fermionic holons and bosonic magnons, which accounts for the doping induced FM phases and topological magnon excitations. We discuss experimental implications for Kitaev candidate materials.
Broad protection and respiratory immunity of dual mRNA vaccination against SARS-CoV-2 variants
Authors: Hajnik Renee L. , Plante Jessica A. , Reddy Bonam Srinivasa , Rafael Grace H. , Liang Yuejin , Hazell Nicholas C. , Walker Jordyn , Reyna Rachel A. , Walker David H. , Alameh Mohamad-Gabriel , Weissman Drew , Weaver Scott C. , Plante Kenneth S. , Hu Haitao
Published: September 2024

While first-generation, spike (S)-based COVID-19 vaccines were effective against early SARS-CoV-2 strains, the rapid evolution of novel Omicron subvariants have substantially reduced vaccine efficacy. As such, broadly protective vaccines against SARS-CoV-2 are needed to prevent future viral emergence. In addition, it remains less clear whether peripheral immunization, especially with mRNA vaccines, elicits effective respiratory immunity. Our group has developed a nucleoside-modified mRNA vaccine expressing the nucleocapsid (N) protein of the ancestral SARS-CoV-2 virus and has tested its use in combination with the S-based mRNA vaccine (mRNA-S). In this study, we examined efficacy of mRNA-N alone or in combination with mRNA-S (mRNA-S+N) against more immune evasive Omicron variants in hamsters. Our data show that mRNA-N alone induces a modest but significant protection against BA.5 and that dual mRNA-S+N vaccination confers complete protection against both BA.5 and BQ.1, preventing detection of virus in the hamster lungs. Analysis of respiratory immune response in mice shows that intramuscular mRNA-S+N immunization effectively induces respiratory S- and N-specific T cell responses in the lungs and in bronchoalveolar lavage (BAL), as well as antigen-specific binding IgG in BAL. Together, our data further support mRNA-S+N as a potential pan-COVID-19 vaccine for broad protection against current and emerging SARS-CoV-2 variants.
Trajectory of the stellar flyby that shaped the outer Solar System
Authors: Pfalzner Susanne , Govind Amith , Portegies Zwart Simon
Published: September 2024

Unlike the Solar System planets, thousands of smaller bodies beyond Neptune orbit the Sun on eccentric (e > 0.1 and i > 3°) orbits. While migration of the giant planets during the early stages of Solar System evolution could have induced substantial scattering of trans-Neptunian objects (TNOs), this process cannot account for the small number of distant TNOs (rp > 60 au) outside the planets’ reach. The alternative scenario of the close flyby of another star can instead produce all these TNO features simultaneously, but the possible parameter space for such an encounter is vast. Here we compare observed TNO properties with thousands of flyby simulations to determine the specific properties of a flyby that reproduces all the different dynamical TNO populations, their locations and their relative abundances, and find that a $$0.{8}_{-0.1}^{+0.1}\,{M}_{\odot }$$

0
.

8

−
0.1

+
0.1

M

⊙

star passing at a distance of rp = 110 ± 10 au, inclined by i = 70°$${\,}_{-10}^{+5}$$

+
5

−
10

, gives a near-perfect match. This flyby also replicates the retrograde TNO population, which has proved difficult to explain. Such a flyby is reasonably frequent; at least 140 million solar-type stars in the Milky Way are likely to have experienced a similar one. In light of these results, we predict that the upcoming Vera Rubin telescope will reveal that distant and retrograde TNOs are relatively common.
A local-to-global emissions inventory of macroplastic pollution
Authors: Cottom Joshua W. , Cook Ed , Velis Costas A.
Published: September 2024

Negotiations for a global treaty on plastic pollution1 will shape future policies on plastics production, use and waste management. Its parties will benefit from a high-resolution baseline of waste flows and plastic emission sources to enable identification of pollution hotspots and their causes2. Nationally aggregated waste management data can be distributed to smaller scales to identify generalized points of plastic accumulation and source phenomena3–11. However, it is challenging to use this type of spatial allocation to assess the conditions under which emissions take place12,13. Here we develop a global macroplastic pollution emissions inventory by combining conceptual modelling of emission mechanisms with measurable activity data. We define emissions as materials that have moved from the managed or mismanaged system (controlled or contained state) to the unmanaged system (uncontrolled or uncontained state—the environment). Using machine learning and probabilistic material flow analysis, we identify emission hotspots across 50,702 municipalities worldwide from five land-based plastic waste emission sources. We estimate global plastic waste emissions at 52.1 [48.3–56.3] million metric tonnes (Mt) per year, with approximately 57% wt. and 43% wt. open burned and unburned debris, respectively. Littering is the largest emission source in the Global North, whereas uncollected waste is the dominant emissions source across the Global South. We suggest that our findings can help inform treaty negotiations and develop national and sub-national waste management action plans and source inventories.
Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis
Authors: Takaoka Minoru , Zhao Xiaohui , Lim Hwee Ying , Magnussen Costan G. , Ang Owen , Suffee Nadine , Schrank Patricia R. , Ong Wei Siong , Tsiantoulas Dimitrios , Sommer Felix , Mohanta Sarajo K. , Harrison James , Meng Yaxing , Laurans Ludivine , Wu Feitong , Lu Yuning , Masters Leanne , Newland Stephen A. , Denti Laura , Hong Mingyang , Chajadine Mouna , Juonala Markus , Koskinen Juhani S. , Kähönen Mika , Pahkala Katja , Rovio Suvi P. , Mykkänen Juha , Thomson Russell , Kaisho Tsuneyasu , Habenicht Andreas J. R. , Clement Marc , Tedgui Alain , Ait-Oufella Hafid , Zhao Tian X. , Nus Meritxell , Ruhrberg Christiana , Taleb Soraya , Williams Jesse W. , Raitakari Olli T. , Angeli Véronique , Mallat Ziad
Published: September 2024

Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2–4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.
Generation of a pancreas derived hydrogel for the culture of hiPSC derived pancreatic endocrine cells
Authors: Berger Constantin , Glaser Markus , Ziegler Anna-Lena , Neukel Valentina , Walz Fabiola , Zdzieblo Daniela
Published: September 2024

Stem cell-derived β-cells (SC-BCs) represent a potential source for curing diabetes. To date, in vitro generated SC-BCs display an immature phenotype and lack important features in comparison to their bona-fide counterparts. Transplantation into a living animal promotes SC-BCs maturation, indicating that components of the in vivo microenvironment trigger final SC-BCs development. Here, we investigated whether cues of the pancreas specific extracellular matrix (ECM) can improve the differentiation of human induced pluripotent stem cells (hiPSCs) towards β-cells in vitro. To this aim, a pancreas specific ECM (PanMa) hydrogel was generated from decellularized porcine pancreas and its effect on the differentiation of hiPSC-derived pancreatic hormone expressing cells (HECs) was tested. The hydrogel solidified upon neutralization at 37 °C with gelation kinetics similar to Matrigel. Cytocompatibility of the PanMa hydrogel was demonstrated for a culture duration of 21 days. Encapsulation and culture of HECs in the PanMa hydrogel over 7 days resulted in a stable gene and protein expression of most β-cell markers, but did not improve β-cell identity. In conclusion, the study describes the production of a PanMa hydrogel, which provides the basis for the development of ECM hydrogels that are more adapted to the demands of SC-BCs.
Investigating the relationship between stereotyping and creativity during marketing campaigns in marketeers and audiences
Authors: Tan Nuoya , Parashar Nimisha , Ahmetoglu Gorkan , Harris Lasana T.
Published: September 2024

Stereotyping others in a creative process may negatively affect creative output, yet there is currently scant empirical evidence of a link between stereotyping and creativity; here, we explore this link in marketing communications. In a quasi-experiment, we introduced a novel intervention to disrupt marketeers’ dependency on stereotypes and boost their creativity. The intervention decreased marketeers’ use of stereotypes when selecting consumer labels—descriptive labels of a typical consumer based on consumer information—while enhancing the creativity of ideas. In another set of online experiments, we asked British residents to rate the creativity of advertisements and purchase intentions toward advertising products with different levels of stereotypical depictions of people. We found a linear relationship between the stereotypical depictions of people in advertisements and perceived creativity. We also observed a potential U-shaped relationship between stereotypical representations of people in advertisements and purchase intention, such that advertisements with low and high stereotypical representations induced greater purchase intention than did those with medium stereotypical representations. Finally, we discuss the psychological mechanisms that potentially link stereotyping and creativity and the implications for marketing communications.
Preoperative prediction of CNS WHO grade and tumour aggressiveness in intracranial meningioma based on radiomics and structured semantics
Authors: Kalasauskas Darius , Kosterhon Michael , Kurz Elena , Schmidt Leon , Altmann Sebastian , Grauhan Nils F. , Sommer Clemens , Othman Ahmed , Brockmann Marc A. , Ringel Florian , Keric Naureen
Published: September 2024

Preoperative identification of intracranial meningiomas with aggressive behaviour may help in choosing the optimal treatment strategy. Radiomics is emerging as a powerful diagnostic tool with potential applications in patient risk stratification. In this study, we aimed to compare the predictive value of conventional, semantic based and radiomic analyses to determine CNS WHO grade and early tumour relapse in intracranial meningiomas. We performed a single-centre retrospective analysis of intracranial meningiomas operated between 2007 and 2018. Recurrence within 5 years after Simpson Grade I-III resection was considered as early. Preoperative T1 CE MRI sequences were analysed conventionally by two radiologists. Additionally a semantic feature score based on systematic analysis of morphological characteristics was developed and a radiomic analysis were performed. For the radiomic model, tumour volume was extracted manually, 791 radiomic features were extracted. Eight feature selection algorithms and eight machine learning methods were used. Models were analysed using test and training datasets. In total, 226 patients were included. There were 21% CNS WHO grade 2 tumours, no CNS WHO grade 3 tumour, and 25 (11%) tumour recurrences were detected in total. In ROC analysis the best radiomic models demonstrated superior performance for determination of CNS WHO grade (AUC 0.930) and early recurrence (AUC 0.892) in comparison to the semantic feature score (AUC 0.74 and AUC 0.65) and conventional radiological analysis (AUC 0.65 and 0.54). The combination of human classifiers, semantic score and radiomic analysis did not markedly increase the model performance. Radiomic analysis is a promising tool for preoperative identification of aggressive and atypical intracranial meningiomas and could become a useful tool in the future.
Formaldehyde quantification using gas chromatography–mass spectrometry reveals high background environmental formaldehyde levels
Authors: Chothia Sara Y. , Emms Vicki L. , Thomas Liam A. , Bulman Natasha F. A. , Monks Paul S. , Cordell Rebecca L. , Hopkinson Richard J.
Published: September 2024

Formaldehyde (HCHO) is a human toxin that is both a pollutant and endogenous metabolite. HCHO concentrations in human biological samples are reported in the micromolar range; however, accurate quantification is compromised by a paucity of sensitive analysis methods. To address this issue, we previously reported a novel SPME–GC–MS-based HCHO detection method using cysteamine as an HCHO scavenger. This method showed cysteamine to be a more efficient scavenger than the widely used O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine, and enabled detection of aqueous HCHO in the nanomolar range and quantification in the micromolar range. However, quantification in this range required immersive extraction of the HCHO-derived thiazolidine, while a high background signal was also observed. Following on from these studies, we now report an optimised head-space extraction SPME–GC–MS method using cysteamine, which provides similarly sensitive HCHO quantification to the immersive method but avoids extensive wash steps and is therefore more amenable to screening applications. However, high background HCHO levels were still observed A Complementary GC–MS analyses using a 2-aza-Cope-based HCHO scavenger also revealed high background HCHO levels; therefore, the combined results suggest that HCHO exists in high (i.e. micromolar) concentration in aqueous samples that precludes accurate quantification below the micromolar range. This observation has important implications for ongoing HCHO quantification studies in water, including in biological samples.
A protein risk score for all-cause and respiratory-specific mortality in non-Hispanic white and African American individuals who smoke
Authors: Moll Matthew , Pratte Katherine A. , Debban Catherine L. , Liu Congjian , Belinsky Steven A. , Picchi Maria , Konigsberg Iain , Tern Courtney , Rijhwani Heena , Hobbs Brian D. , Silverman Edwin K. , Tesfaigzi Yohannes , Rich Stephen S. , Manichaikul Ani , Rotter Jerome I. , Bowler Russel P. , Cho Michael H.
Published: September 2024

Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31–2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein–protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts.
The value of error-correcting responses for cognitive assessment in games
Authors: Markovitch Benny , Evans Nathan J. , Birk Max V.
Published: September 2024

Traditional conflict-based cognitive assessment tools are highly behaviorally restrictive, which prevents them from capturing the dynamic nature of human cognition, such as the tendency to make error-correcting responses. The cognitive game Tunnel Runner measures interference control, response inhibition, and response-rule switching in a less restrictive manner than traditional cognitive assessment tools by giving players movement control after an initial response and encouraging error-correcting responses. Nevertheless, error-correcting responses remain unused due to a limited understanding of what they measure and how to use them. To facilitate the use of error-correcting responses to measure and understand human cognition, we developed theoretically-grounded measures of error-correcting responses in Tunnel Runner and assessed whether they reflected the same cognitive functions measured via initial responses. Furthermore, we evaluated the measurement potential of error-correcting responses. We found that initial and error-correcting responses similarly reflected players’ response inhibition and interference control, but not their response-rule switching. Furthermore, combining the two response types increased the reliability of interference control and response inhibition measurements. Lastly, error-correcting responses showed the potential to measure response inhibition on their own. Our results pave the way toward understanding and using post-decision change of mind data for cognitive measurement and other research and application contexts.
Elastin-like polypeptide coacervates as reversibly triggerable compartments for synthetic cells
Authors: Chen Chang , Ganar Ketan A. , de Haas Robbert J. , Jarnot Nele , Hogeveen Erwin , de Vries Renko , Deshpande Siddharth
Published: September 2024

Compartmentalization is a vital aspect of living cells to orchestrate intracellular processes. In a similar vein, constructing dynamic and responsive sub-compartments is key to synthetic cell engineering. In recent years, liquid-liquid phase separation via coacervation has offered an innovative avenue for creating membraneless organelles (MOs) within artificial cells. Here, we present a lab-on-a-chip system to reversibly trigger peptide-based coacervates within cell-mimicking confinements. We use double emulsion droplets (DEs) as our synthetic cell containers while pH-responsive elastin-like polypeptides (ELPs) act as the coacervate system. We first present a high-throughput microfluidic DE production enabling efficient encapsulation of the ELPs. The DEs are then harvested to perform multiple MO formation-dissolution cycles using pH as well as temperature variation. For controlled long-term visualization and modulation of the external environment, we developed an integrated microfluidic device for trapping and environmental stimulation of DEs, with negligible mechanical force, and demonstrated a proof-of-principle osmolyte-based triggering to induce multiple MO formation-dissolution cycles. In conclusion, our work showcases the use of DEs and ELPs in designing membraneless reversible compartmentalization within synthetic cells via physicochemical triggers. Additionally, presented on-chip platform can be applied over a wide range of phase separation and vesicle systems for applications in synthetic cells and beyond.
Heavier tetrylene- and tetrylyne-transition metal chemistry: it's no carbon copy
Authors: Hadlington Terrance J.
Published: September 2024

Developments in synthetic methods for and reactivity of heavier tetrylene and tetrylyne complexes of the d-block elements are summarised, with a view towards cooperative bond activation and utilisation in catalysis.
Portable and simultaneous detection of four respiratory pathogens through a microfluidic LAMP and real-time fluorescence assay
Authors: Liu Junwen , Zeng Zhi , Li Feina , Jiang Bo , Nie You , Zhang Guohao , Pang Biao , Sun Lin , Hao Rongzhang
Published: September 2024

Portable detection of four respiratory pathogens through microfluidic real-time LAMP assay.