bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in silico analyses reveal the interaction between LysM receptor‐like kinase3 of Solanum tuberosum and the carbohydrate elicitor Riclin octaose
Authors: Wang Hongyang , Zhang Ruixin , Hu Junpeng , Fu Renjie , Li Jing
Published: October 2023

As a carbohydrate elicitor, Riclin octaose (Rioc) activates the pattern‐triggered immunity of Solanum tuberosum L., while how the plant perceives Rioc is unknown. Here, a pattern recognition receptor StLYK3 (LysM receptor‐like kinase3) whose transcription level was significantly up‐regulated after Rioc elicitation was investigated in vitro and in silico. The nucleotide that encoded the ectodomain of StLYK3 (StLYK3‐ECD) was heterologously expressed in the Pichia pastoris strain GS115. The purified StLYK3‐ECD had the molecular weight of 25.08 kDa and pI of 5.69. Afterwards interaction between StLYK3‐ECD and Rioc was analyzed by isothermal titration calorimetry. The molar ratio of ligand to receptor, dissociation constant, and enthalpy were 1.28 ± 0.04, 26.7 ± 3.1 μM, and −45.0 ± 1.8 kJ mol−1, respectively. Besides, molecular dynamics results indicated that StLYK3‐ECD contained three carbohydrate‐binding motifs and the first two motifs probably contributed to the interaction with Rioc via hydrogen bond and van de Waals’ forces. Amino acids containing hydroxyl, amidic, and sulfhydryl groups took the main portion in the docking site. Moreover, replacing the 92nd threonyl (T) of StLYK3‐ECD with valyl (V) resulted in the alteration of the preferred docking site. The dissociation constant drastically increased to 841.6 ± 232.4 μM. In conclusion, StLYK3 was a potential receptor of Rioc.
Enhanced anti‐tumor activity of arginine decarboxylase through the incorporation of aromatic amino acids at the multimer‐forming interface
Authors: Park Min Yeong , Kim Seoungkyun , Kwon Na Hyun , Moon Giseok , Cha Jaehyun , Kwon Inchan
Published: October 2023

The pressing challenge of cancer's high mortality and invasiveness demands improved therapeutic approaches. Targeting the nutrient dependencies within cancer cells has emerged as a promising approach. This study is dedicated to demonstrating the potential of arginine depletion for cancer treatment. Notably, the focus centers on arginine decarboxylase (RDC), a pH‐dependent enzyme expecting enhanced activity within the slightly acidic microenvironments of tumors. To investigate the effect of a single‐site mutation on the catalytic efficacy of RDC, diverse amino acids, including glycine, alanine, phenylalanine, tyrosine, tryptophan, p‐azido‐phenylalanine, and a phenylalanine analog with a hydrogen‐substituted tetrazine, were introduced at the crucial threonine site (position 39) in the multimer‐forming interface. Remarkably, the introduction of either a natural or a non‐natural aromatic amino acid at position 39 substantially boosted enzymatic activity, while amino acids with smaller side chains did not show the same effect. This enhanced enzymatic activity is likely attributed to the reinforced formation of multimer structures through favorable interactions between the introduced aromatic amino acid and the neighboring subunit. Noteworthy, at slightly acidic pH, the RDC variant featuring tryptophan at position 39 demonstrated augmented cytotoxicity against tumor cells compared to the wild‐type RDC. This attribute aligns with the tumor microenvironment and positions these variants as potential candidates for targeted cancer therapy.
Attack of the clones: Unveiling subclonal/heterogenous mismatch repair/microsatellite instability status in endometrial cancer
Authors: Grither Whitney R. , Hagemann Ian S. , Powell Matthew A. , Mullen Mary M.
Published: October 2023

Any time there are two or more tests for a given analyte, there will be some degree of disagreement between them. This editorial contextualizes the recent findings by Riedinger and colleagues regarding discordant mismatch repair and microsatellite instability testing in endometrial cancer.
Stage IV breast, colorectal, and lung cancer at diagnosis in adults living with intellectual or developmental disabilities: A population‐based cross‐sectional study
Authors: Mahar Alyson L. , Biggs Kelly , Hansford Rebecca L. , Derksen Shelley , Griffiths Rebecca , Enns Jennifer E. , Dawe David E. , Hallet Julie , Kristjanson Mark , Decker Kathleen , Cobigo Virginie , Shooshtari Shahin , Stirling Morgan , Kelly Christine , Brownell Marni , Turner Donna , Ouellette‐Kuntz Hélène
Published: October 2023

Background

Cancer is a leading cause of death among people living with intellectual or developmental disabilities (IDD). Although studies have documented lower cancer screening rates, there is limited epidemiological evidence quantifying potential diagnostic delays. This study explores the risk of metastatic cancer stage for people with IDD compared to those without IDD among breast (female), colorectal, and lung cancer patients in Canada.

Methods

Separate population‐based cross‐sectional studies were conducted in Ontario and Manitoba by linking routinely collected data. Breast (female), colorectal, and lung cancer patients were included (Manitoba: 2004–2017; Ontario: 2007–2019). IDD status was identified using established administrative algorithms. Modified Poisson regression with robust error variance models estimated associations between IDD status and the likelihood of being diagnosed with metastatic cancer. Adjusted relative risks were pooled between provinces using random‐effects meta‐analyses. Potential effect modification was considered.

Results

The final cohorts included 115,456, 89,815, and 101,811 breast (female), colorectal, and lung cancer patients, respectively. Breast (female) and colorectal cancer patients with IDD were 1.60 and 1.44 times more likely to have metastatic cancer (stage IV) at diagnosis compared to those without IDD (relative risk [RR], 1.60; 95% confidence interval [CI], 1.16–2.20; RR, 1.44; 95% CI, 1.24–1.67). This increased risk was not observed in lung cancer. Significant effect modification was not observed.

Conclusions

People with IDD were more likely to have stage IV breast and colorectal cancer identified at diagnosis compared to those without IDD. Identifying factors and processes contributing to stage disparities such as lower screening rates and developing strategies to address diagnostic delays is critical.
Prognostic impact of lymph node involvement and loss of heterozygosity of 1p or 16q in stage III favorable histology Wilms tumor: A report from Children’s Oncology Group Studies AREN03B2 and AREN0532
Authors: Evageliou Nicholas , Renfro Lindsay A. , Geller James , Perlman Elizabeth , Kalapurakal John , Paulino Arnold , Dix David , Eklund Meryle J. , Murphy Andrew J. , Romao Rodrigo L. P. , Ehrlich Peter F. , Varela Carly R. , Vallance Kelly , Fernandez Conrad V. , Dome Jeffrey S. , Mullen Elizabeth A.
Published: October 2023

Introduction

The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone.

Patients and Methods

A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)–treated patients met inclusion criteria. Event‐free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2‐only patients with unknown outcomes or treatment other than DD4A were excluded.

Results

EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR], 2.12; p = .0037), LN positivity (HR, 2.78; p = .0002), LOH 1p (HR, 2.18; p = .0067), and LOH 16q (HR, 1.72; p = .042) were associated with worse EFS. Compared with patients with both LN– and LOH–, those with negative nodes but positive LOH 1p or 16q and those with LN+ but LOH– for 1p or 16q had significantly worse EFS (HR, 3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR, 6.33; overall group factor, p < .0001).

Conclusion

Findings confirm LN+ status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial.
π‐shaped circularly polarized high‐gain Minkowski fractal antenna for radar applications
Authors: Pandav Subhasish , Sadhukhan Gautam , Das Tanmaya Kumar , Behera Santanu Kumar , Mohanty Madhusmita
Published: October 2023

This article investigates a compact π‐shaped circularly polarized Minkowski fractal antenna (MFA). The proposed radiator is taking a π‐shape with semicircular cuts along the opposite side of the patch with a V‐cut at the bottom. A second‐order Minkowski fractal curve is implemented on the bottom ground plane. The antenna element is powered by a coaxial probe. The asymmetric structure generates two orthogonal modes, which results in circular polarization. A maximum gain response of 7.1 dBic is observed in the impedance band width (IBW) covering 9.7 to 11.2 GHz. The patch is fabricated on substrate RT/Duroid 5880™ (𝜀𝑟=2.2). The antenna has a compact dimension of 0.90λ0 × 0.90λ0 × 0.05λ0 (fr = 10.45 GHz). A good match in the results validates the simulated and measured data in comparison with the existing models from literature with respect to diversity performance, thus making it suitable for radar applications.
[Ru3(CN)3(CO)9]3−:Building Block for Multimetallic Cages
Authors: Wang Ping , Zhang Yu , Woods Toby , Rauchfuss Thomas B.
Published: October 2023

A cluster‐ligand is disclosed in the form of [Ru3(CN)3(CO)9]3− ([1]3−). Produced by simple reaction of [Ru3(CO)12] with cyanide, [1]3− serves as a precursor to a series of μ‐CN cages. When treated with [Ru3(CO)12], it readily forms the prism [Ru6(μ‐CN)3(CO)18]3−. With 1.5 equiv. of [Cu(MeCN)4]+ [1]3− reacts to give the expanded prism {Cu3[Ru3(μ‐CN)3(CO)9]2}3−, which features three two‐coordinate Cu(I) centers. Sources of Ni2+ and Fe2+ bind two equivalents of [1]3−, giving the double cages {M[Ru3(μ‐CN)3(CO)9]2}4− (M=Ni, Fe) wherein the central metal is octahedral. The 1 : 1 reaction using [Fe(H2O)6]2+ gave the interpenetrated super‐tetrahedrane {Fe4(μ4‐O)[Ru3(μ‐CN)3(CO)9]4}4−.
Photoredox Synthesis of Silyl Ethers via Radical Coupling of Ketones with Hydrosilanes and [1, 2]‐Brook Rearrangement
Authors: Wang Ting , Wang Guo‐Qin , Zhang Yue , Liu Yuan‐Yuan , Zhang Zheng‐Bing , Han Pan , Jing Lin‐Hai
Published: October 2023

An expedient synthesis of silyl ethers is reported via photocatalytic free radical coupling of ketones with hydrosilanes and subsequent [1, 2]‐Brook rearrangement. This strategy features the advantages of 100 % atom economy, environmental friendliness, easily available starting materials as well as late‐stage functionalization of complex molecules.
Eye movement desensitisation and reprocessing as add‐on treatment to enhanced cognitive behaviour therapy for patients with anorexia nervosa reporting childhood maltreatment: A quasi‐experimental multicenter study
Authors: Rossi Eleonora , Cassioli Emanuele , Cecci Lucia , Arganini Francesca , Martelli Michela , Redaelli Carolina Alberta , Anselmetti Simona , Bertelli Sara , Fernandez Isabel , Ricca Valdo , Castellini Giovanni
Published: October 2023

Objective

This quasi‐experimental study aimed to compare the outcome of patients with Anorexia Nervosa (AN) reporting moderate/severe childhood maltreatment (CM) treated exclusively with Enhanced Cognitive Behaviour Therapy (CBT‐E) or with CBT‐E plus Eye Movement Desensitisation and Reprocessing (EMDR).

Method

A total of 75 patients with AN reporting moderate/severe CM were initially assessed regarding body mass index (BMI), general and eating disorder (ED)‐specific psychopathology, and dissociative symptoms, and re‐evaluated after 40 CBT‐E sessions (T1). Then, 18 patients received EMDR, whereas the others were placed on a waiting list and continued CBT‐E. T2 assessment was performed after 20–25 sessions of EMDR or CBT‐E. A control group of 67 patients without CM was also enroled and treated with CBT‐E.

Results

Contrary to patients without CM, neither of the traumatised groups improved in BMI, general and ED psychopathology, or dissociation at T1. However, at T2, both traumatised groups improved in BMI and ED‐specific psychopathology, with the CBT + EMDR group demonstrating greater improvements. Moreover, only the CBT + EMDR group improved in general psychopathology and dissociative symptoms. The reduction of ED symptoms in traumatised patients was mediated by the amelioration of dissociation.

Discussion

The addition of EMDR to CBT‐E may benefit patients with AN reporting moderate/severe CM.
Naturalization and immigrants' health
Authors: Aparicio Fenoll Ainoa
Published: October 2023

The “healthy immigrant effect” refers to the well‐documented fact that immigrants are healthier than natives upon arrival, but their health level converges to that of natives over time. Unfortunately, we know little about whether environmental, institutional, or selective return migration mechanisms are behind the convergence. In this paper, I test whether immigrants' naturalization influences health convergence speed. Using restricted‐access Spanish health data from the National and European Health Surveys, I estimate the impact of naturalization on health by exploiting that naturalization is possible after 2 years of residence for immigrants from specific countries and after 10 years for all other immigrants. I find that naturalization worsens immigrants' health and thus accelerates the speed of convergence to natives' health. Increases in employment are potential mechanisms behind this effect.
Local delivery of adeno‐associated viral vectors with electrospun gelatin nanofiber mats
Authors: Furuno Kotoko , Elvitigala Kelum Chamara Manoj Lakmal , Suzuki Keiichiro , Sakai Shinji
Published: October 2023

Adeno‐associated viral (AAV) vectors play a significant role in gene therapy, yet the typical delivery methods, like systemic and local AAV injections, often lead to unintended off‐target distribution and tissue damage due to injection. In this study, we propose a localized delivery approach for AAV vectors utilizing electrospun gelatin nanofiber mats, which are cross‐linked with glutaraldehyde. The AAV vectors, which encoded a green fluorescent protein (GFP), were loaded onto the mats by immersing them in a solution containing the vectors. The amount of AAV vector loaded onto the mats increased as the vector concentration in the solution increased. The loaded AAV vector was steadily released into the cell culture medium over 3 days. The mats incubated for 3 days also showed the ability to transduce into the cells cultured on them. We evaluated the effectiveness of this delivery system by attaching the mats to mouse livers. GFP expression was visible on the surface of the liver beneath the attached mats, but not in areas in direct contact with the mats. These findings suggest that the attachment of AAV vector‐loaded electrospun gelatin nanofiber mats to a target site present a promising solution for localized gene delivery while reducing off‐target distribution.
Adropin may promote insulin stimulated steroidogenesis and spermatogenesis in adult mice testes
Authors: Tripathi Shashank , Maurya Shweta , Singh Ajit
Published: October 2023

Adropin is a versatile peptide which was discovered as a novel metabolic hormone that is involved in the regulation of lipid and glucose homeostasis. However, its possible role in the testicular function is not yet understood. The aim of our study was to explore the distribution pattern of adropin and GPR19 in various cell types and its possible role in testicular functions of adult mice. Immunohistochemical study revealed the intense immunoreactivity of adropin in the Leydig cells, while GPR19 showed intense immunoreactivity in the pachytene spermatocytes and mild immunoreactivity in Leydig cells and primary as well as secondary spermatocytes in mouse testis. Enho mRNA was also found to be expressed in the mouse testis. These findings suggested that adropin‐GPR19 signaling may act in autocrine/paracrine manner to modulate testicular functions. Furthermore, to find out the direct role of adropin in the testicular function, in vitro study was performed in which testicular slices were cultured with adropin alone (10 and 100 ng/mL) and in combination with insulin (5 μg/mL). Adropin alone inhibited testicular testosterone synthesis by inhibiting the expression of P450‐SCC, 3β‐HSD, and 17β‐HSD while along with insulin stimulated the testicular testosterone synthesis by increasing the expression of GPR19, IR, StAR, P450‐SCC, 3β‐HSD, and 17β‐HSD. Adropin alone or in combination with insulin promoted germ cell survival and proliferation by upregulating the expression of PCNA, Bcl2, and pERK1/2. Thus, it can be concluded that adropin‐GPR19 signaling promotes insulin stimulated steroidogenesis and germ cell survival as well as proliferation in the mice testes in an autocrine/paracrine manner.
Improvement of neurogenic urinary dysfunctions in female rats treated with an injection of botulinum toxin A at the epicenter of the spinal cord injured site
Authors: Gandara Cynthia K. , Palacios Jose L. , Luis Quintanar J. , Zhang Yingchun , Li Xuhong , Munoz Alvaro
Published: October 2023

Objective

To assess the effect of an injection of botulinum toxin A (BoNT/A) at the epicenter of the spinal cord injury (SCI) site on the recovery of lower urinary tract function in female rats with thoracic SCI.

Materials and Methods

Twenty‐four female Wistar rats with Sham (laminectomy at T8/T9 level) or SCI (at T8/T9; 30 g compression for 5 s) were assigned into Sham‐SS (injected with 5 µL of saline solution), Sham‐BoNT/A (injected with 15 pg/rat, equivalent to 7.5 Units/kg of BoNT/A in 5 µL volume), SCI‐SS (injured and injected with saline), SCI‐BoNT/A (injured and injected with BoNT/A), N = 6 per group. Weekly evaluation of stereotyped micturition behavior, hind‐limb nociception, and locomotor activity was performed 1 week before and during 6 weeks after surgery. Subsequently, all groups underwent simultaneous electromyography of the external urethral sphincter (EUS‐EMG) and cystometric (CMG) studies.

Results

A compression SCI at the T8/T9 thoracic level significantly impairs sensory and locomotive functions, as well as stereotyped micturition behavior. However, these impairments were improved by BoNT/A injection after SCI. Neither injections of saline solution nor BoNT/A had an appreciable effect on the same parameters evaluated in the Sham groups. The combined EUS‐EMG and CMG evaluations revealed important improvements of lower urinary tract physiology, particularly a reduction in the frequency of non‐voiding contractions and the properties of EUS bursting activity indicated as the amplitude of the EUS‐EMG signal and duration of burst electrical activity during effective voiding.

Conclusion

The severe impairments on sensory and locomotive functions as well stereotyped micturition caused by an SCI could be potentially attenuated by an injection of a small amount of BoNT/A directly into the epicenter of the SCI region. A reduction in the release of neurotoxic neurotransmitters requiring the SNARE complex may be the mechanism triggered by BoNT/A to reduce neurotoxicity and hyperexcitability created in the SCI area to improve the survival of spinal cord cells involved in micturition.
Registration of Golden Promise/Otis barley recombinant inbred line mapping population
Authors: Bregitzer Phil , Ajayi Oyeyemi , Gao Dongying , Esvelt Klos Kathy , Mahalingam Ramamurthy
Published: October 2023

A recombinant inbred line mapping population was developed from a cross between the heritage malting barley (Hordeum vulgare ssp. vulgare) cultivar ‘Golden Promise’ and ‘Otis’, a feed barley cultivar developed in the 1960s suitable for the high dry plains. The Golden Promise/Otis recombinant inbred line (RIL) population (MP‐3, NSL 545640 MAP) consists of 190 F5:7 individuals. The parental lines exhibited significant differences in several agronomic traits including height, heading date, yield/plant, and lodging. Transgressive segregation in the RILs was evidenced by the broad range of values observed for these agronomic traits. The RIL population was genotyped using the Illumina 50k iSelect single nucleotide polymorphism (SNP) arrays. Of the 10,810 polymorphic markers that were identified between the two parents, 4617 markers were used for generating a genetic map that spanned 4566 cM with an average distance of 1 cM between markers. The fact that Golden Promise is a malting cultivar developed in the United Kingdom, versus Otis, a feed barley bred in the United States for dryland cultivation, indicates that this population may be useful in identifying the genetic basis of many other traits.
PTM‐Psi: A python package to facilitate the computational investigation of post‐translational modification on protein structures and their impacts on dynamics and functions
Authors: Mejia‐Rodriguez Daniel , Kim Hoshin , Sadler Natalie , Li Xiaolu , Bohutskyi Pavlo , Valiev Marat , Qian Wei‐Jun , Cheung Margaret S.
Published: October 2023

Post‐translational modification (PTM) of a protein occurs after it has been synthesized from its genetic template, and involves chemical modifications of the protein's specific amino acid residues. Despite of the central role played by PTM in regulating molecular interactions, particularly those driven by reversible redox reactions, it remains challenging to interpret PTMs in terms of protein dynamics and function because there are numerous combinatorially enormous means for modifying amino acids in response to changes in the protein environment. In this study, we provide a workflow that allows users to interpret how perturbations caused by PTMs affect a protein's properties, dynamics, and interactions with its binding partners based on inferred or experimentally determined protein structure. This Python‐based workflow, called PTM‐Psi, integrates several established open‐source software packages, thereby enabling the user to infer protein structure from sequence, develop force fields for non‐standard amino acids using quantum mechanics, calculate free energy perturbations through molecular dynamics simulations, and score the bound complexes via docking algorithms. Using the S‐nitrosylation of several cysteines on the GAP2 protein as an example, we demonstrated the utility of PTM‐Psi for interpreting sequence–structure–function relationships derived from thiol redox proteomics data. We demonstrate that the S‐nitrosylated cysteine that is exposed to the solvent indirectly affects the catalytic reaction of another buried cysteine over a distance in GAP2 protein through the movement of the two ligands. Our workflow tracks the PTMs on residues that are responsive to changes in the redox environment and lays the foundation for the automation of molecular and systems biology modeling.
Dose‐related clozapine‐induced weight gain
Authors: Lam Y. W. Francis
Published: October 2023

Weight gain is a known adverse drug reaction associated with the use of antipsychotic medications, potentially leading to obesity and/or other long‐term metabolic complications such as type II diabetes, hypertension, and cardiovascular disease. Reported risk factors associated with antipsychotic‐induced weight gain include young age, female sex, and low baseline body mass index (Correll et al., 2017). Among the approaches used to reverse or reduce weight gain associated with antipsychotics are non‐pharmacological interventions around diet and exercise and pharmacological strategies involving either switching to a different antipsychotic, adding metformin or other weight‐lowering drugs, or reducing the dose of the current antipsychotic.
Studies on the load‐carrying behaviour of steel‐to‐concrete joints with headed studs for normal and shear loads
Authors: Ruopp Jakob , Kuhlmann Ulrike
Published: October 2023

Steel and composite structures usually have interfaces to concrete walls or concrete foundations. The design and verification of the interaction between steel and concrete is challenging because the load‐carrying behaviour as well as the different material properties have to be taken into account. Steel‐to‐concrete joints can be realised economically and with comparatively little effort by using fasteners such as headed studs for the anchorage in the concrete. Recent investigations have shown that a holistic verification of joints is possible, if the concrete failure mechanisms are integrated into the concept of the component method of steel and composite structures. This allows an economical verification that is competitive with pure concrete solutions because the load‐carrying behaviour in the concrete is captured with the concrete components and the steel components of the joints do not have to be oversized to avoid failure in the concrete. The load‐carrying capacity of the steel‐to‐concrete joints can effectively be improved by taking into account the reinforcement which allows for a significant increase of the resistance of the concrete components. By arranging the reinforcement in the area of the fasteners, it is possible to achieve a higher load‐carrying capacity and, with a suitable design of the reinforcement, also a ductile behaviour of the joint. In the following article, joints are described that were studied in the dissertation (Ruopp, 2020) and were investigated with regard to the above‐mentioned aspects. The article concludes with an outlook on the normative implementation.
A Multiscale Numerical Simulation of Quasi-Two-Dimensional Bacterial Turbulence Using a Regularized Stokeslet Representation
Authors: Ishimoto Kenta
Published: October 2023

Self-propelled particles in low-Reynolds-number flow interact through the surrounding fluid. This study examined the collective dynamics of model bacterial swimmers in which a collection of regularized Stokeslets and rotlets captured their surrounding near-field flow. With the hydrodynamic and steric repulsive interactions, the numerical simulation of the swimming cells in a two-dimensional plane reproduced well-known turbulence-like dynamics, characterized by coherent collective vortex dynamics, agreeing with the previous. Furthermore, we incorporated two parallel free-slip boundaries to consider the impact of geometrical confinement. We observed that the size of the vortices of bacterial turbulence attained its maximal value when the width of the two boundaries was of the same order as the swimmer length. The rotlet term induces chiral swimming trajectories in the presence of confines for a dilute suspension. In a dense turbulence suspension, however, we observed that the chiral dynamics are subdued.
A Dynamic Extreme Value Model with Application to Volcanic Eruption Forecasting
Authors: Nguyen Michele , Veraart Almut E. D. , Taisne Benoit , Tan Chiou Ting , Lallemant David
Published: October 2023

Extreme events such as natural and economic disasters leave lasting impacts on society and motivate the analysis of extremes from data. While classical statistical tools based on Gaussian distributions focus on average behaviour and can lead to persistent biases when estimating extremes, extreme value theory (EVT) provides the mathematical foundations to accurately characterise extremes. This motivates the development of extreme value models for extreme event forecasting. In this paper, a dynamic extreme value model is proposed for forecasting volcanic eruptions. This is inspired by one recently introduced for financial risk forecasting with high-frequency data. Using a case study of the Piton de la Fournaise volcano, it is shown that the modelling framework is widely applicable, flexible and holds strong promise for natural hazard forecasting. The value of using EVT-informed thresholds to identify and model extreme events is shown through forecast performance, and considerations to account for the range of observed events are discussed.
Estimation of reference evapotranspiration based on machine learning models and timeseries analysis: a case study in an arid climate
Authors: Hendy Zeinab M. , Abdelhamid Mahmoud A. , Gyasi-Agyei Yeboah , Mokhtar Ali
Published: October 2023

Water scarcity is a major challenge for irrigated agriculture, particularly in developing countries where access to meteorological data for calculating reference evapotranspiration (ETo) is limited. Thus, this study explores the potential of two machine learning models (random forest (RF) and long short-term memory (LSTM)) and autoregressive integrated moving average (ARIMA) to forecast ETo. The investigation was conducted for four weather stations in Egypt, from 1982 to 2020. The machine learning models were evaluated using four combinations of inputs: maximum and minimum temperature, relative humidity, and wind speed. The best results for both RF and LSTM models were achieved with the first set of inputs that included all four variables at both regional and local scales. For the regional scale, RF and LSTM models achieved R2 values of 0.85 and 0.86, respectively, with RMSE values of 0.69 and 0.68 mm/day. At the local scale, RF and LSTM models exhibited R2 values ranging from 0.92 to 0.95 and 0.93 to 0.95, respectively, while RMSE ranged between 0.38 and 0.46 mm/day and 0.37–0.43 mm/day, respectively. Additionally, ARIMA models were employed for tim series analysis of the same ETo data. ARIMA (2,1,4) and ARIMA (2,1,3) were found to be the most suitable models for the local-scale analysis while ARIMA (2,1,4) was identified as the optimal model for the regional-scale analysis. For the local-scale analysis, R2 values ranged from 0.86 to 0.91 and RMSE values ranged from 0.26 to 0.38. The regional scale analysis yielded an R2 value of 0.89 and an RMSE value of 0.58 mm/day. The developed models can be used in places where meteorological data for forecasting ETo are limited.
Combining the potential of 3D printed buccal films and nanostructured lipid carriers for personalised cannabidiol delivery
Authors: Abdella Sadikalmahdi , Kim Sangseo , Afinjuomo Franklin , Song Yunmei , Upton Richard , Garg Sanjay
Published: October 2023

Cannabidiol (CBD) has been recognized for its numerous therapeutic benefits, such as neuroprotection, anti-inflammatory effects, and cardioprotection. However, CBD has some limitations, including unpredictable pharmacokinetics and low oral bioavailability. To overcome the challenges associated with CBD delivery, we employed Design of Experiments (DoE), lipid carriers, and 3D printing techniques to optimize and develop buccal film loaded with CBD-NLCs. Three-factor Box-Behnken Design was carried out to optimise the NLCs and analyse the effect of independent factors on dependent factors. The emulsification-ultrasonication technique was used to prepare the NLCs. A pressure-assisted micro-syringe printing technique was used to produce the films. The produced films were studied for physicochemical, and mechanical properties, release profiles, and predicted in vivo performance. The observed particle size of the NLCs ranged from 12.17 to 84.91 nm whereas the PDI varied from 0.099 to 0.298. Lipid and sonication time positively affected the particle size whereas the surfactant concentration was inversely related. CBD was incorporated into the optimal formulation and the observed particle size, PDI, and zeta potential for the CBD-NLCs were 94.2 ± 0.47 nm, 0.11 ± 0.01 and − 11.8 ± 0.52 mV. Hydroxyethyl cellulose (HEC)-based gel containing the CBD-NLCs was prepared and used as a feed for 3D printing. The CBD-NLCs film demonstrated a slow and sustained in vitro release profile (84. 11 ± 7.02% in 6 h). The predicted AUC0–10 h, Cmax, and Tmax were 201.5 µg·h/L, 0.74 µg/L, and 1.28 h for a film with 0.4 mg of CBD, respectively. The finding demonstrates that a buccal film of CBD-NLCs can be fabricated using 3D printing.

Graphical Abstract
Learning from Other Religions
Authors: Brown David
Published: October 2023

One common argument against taking the notion of divine revelation seriously is the extraordinrary diversity which exists betwen the world's major religions. How can God be thought to have spoken to humanity when the conclusions drawn are so very different? David Brown authoritatively and persuasively tackles this issue head-on. He refutes the idea that all faiths necessarily culminate in Christianity, or that they can be reduced to some facile lowest common denominator, arguing instead that ideas may emerge more naturally in one context than another. Sometimes, because of its own singular situation, another religion has proved to be more perceptive on a particular issue than Christianity. At other times, no religion will hold the ultimate answer because what can be asserted is heavily dependent on what is viable both scientifically and philosophically. Although complete reconciliation is impossible, a richer notion of revelation – so the author suggests – can be the result.
Global Mapping of Microwave Emissivity and Emitting Depth in Arid Areas Using GMI Observations
Authors: Favrichon Samuel , Prigent Catherine , Jimenez Carlos , Vogt Roland
Published: October 2023

Over arid areas, observations of brightness temperatures by passive microwave radiometers are affected by the variation of the emitting depth with wavelengths. When this variation is unaccounted for, it limits the assimilation of passive microwaves over deserts in Numerical Weather Prediction models and it causes large errors in passive microwave retrievals of land surface temperatures. The emitting depths, along with the corresponding emissivities, are estimated from 10 to 89 GHz, using the non‐Sun‐synchronous observations of the Global Precipitation Mission Microwave Imager to reconstruct the monthly diurnal cycle of brightness temperature. The soil temperature profile is modeled using a two‐term Fourier decomposition based on the ERA5 surface temperature. The combination of the observation and the modeled temperature allows for an estimation of the microwave effective emitting depth. The emitting depth is estimated to be up to 25 cm at 36 GHz, resulting in large differences between the surface temperature and the effective emitting temperature. The variation of emitting depth with frequency is parameterized, and a companion data set provides the necessary parameters to calculate the emitting depth for arid areas between 10 and 89 GHz, globally. The benefit of this parameterization is quantified, with an application to the modeling of observations from the Special Sensor Microwave Imager Sounder over arid areas.
Runoff Threshold Responses in Continental Boreal Catchments: Nexus of Subhumid Climate, Low‐Relief, Surficial Geology, and Land Cover
Authors: Devito K. J. , O’Sullivan A. M. , Peters D. L. , Hokanson K. J. , Kettridge N. , Mendoza C. A.
Published: October 2023

We examined annual runoff from 20 meso‐scale catchments over 25 years, to elucidate how interactions between physiography and long‐term weather patterns influence the magnitude of spatial–temporal thresholds in annual runoff responses in water‐limited, low‐relief, glaciated continental Boreal landscapes. Annual runoff ranged over 2 orders of magnitude (<3 to >300 mm) among catchments receiving similar annual precipitation. Threshold relationships were observed with cumulative regional moisture deficits that reflected spatial–temporal differences in effective storage and antecedent moisture among catchments with differing portions of glacial‐deposit and land‐cover types. The importance of the glacial‐deposit texture and forest‐peatland cover on runoff behavior among catchments varied with weather patterns and catchment antecedent moisture states. Dry states yielded low annual runoff that ranged by 2 orders of magnitude (0–80 mm), with higher values in catchments with predominantly coarse‐textured deposits. During near normal antecedent moisture, annual runoff remained low (<10 mm) in catchments associated with fine‐textured, hummocky landforms and deciduous forests. Annual runoff >10 mm was observed only in catchments with extensive peatlands. Infrequent wet states resulted in increased runoff in all catchments; however, ranges in maximum runoff were associated with heterogeneity in catchment landforms and land covers. Integrating cumulative precipitation with the proportion of glacial‐deposit and land‐cover types within catchments can (a) represent water cycling and regional sink‐source dynamics controlling runoff and (b) provide an effective management framework for predicting climate and land use impacts on regional runoff in water‐limited, low‐relief, glaciated landscapes such as the Boreal Plain.
Self-reported childhood family adversity is linked to an attenuated gain of trust during adolescence
Authors: Reiter Andrea M. F. , Hula Andreas , Vanes Lucy , Hauser Tobias U. , Kokorikou Danae , Goodyer Ian M. ,   NSPN Consortium,   NSPN Principle Investigators,   NSPN staff, Fonagy Peter , Moutoussis Michael , Dolan Raymond J.
Published: October 2023

A longstanding proposal in developmental research is that childhood family experiences provide a template that shapes a capacity for trust-based social relationships. We leveraged longitudinal data from a cohort of healthy adolescents (n = 570, aged 14–25), which included decision-making and psychometric data, to characterise normative developmental trajectories of trust behaviour and inter-individual differences therein. Extending on previous cross-sectional findings from the same cohort, we show that a task-based measure of trust increases longitudinally from adolescence into young adulthood. Computational modelling suggests this is due to a decrease in social risk aversion. Self-reported family adversity attenuates this developmental gain in trust behaviour, and within our computational model, this relates to a higher ‘irritability’ parameter in those reporting greater adversity. Unconditional trust at measurement time point T1 predicts the longitudinal trajectory of self-reported peer relation quality, particularly so for those with higher family adversity, consistent with trust acting as a resilience factor.
Linking climate warming and land conversion to species’ range changes across Great Britain
Authors: Suggitt Andrew J. , Wheatley Christopher J. , Aucott Paula , Beale Colin M. , Fox Richard , Hill Jane K. , Isaac Nick J. B. , Martay Blaise , Southall Humphrey , Thomas Chris D. , Walker Kevin J. , Auffret Alistair G.
Published: October 2023

Although increased temperatures are known to reinforce the effects of habitat destruction at local to landscape scales, evidence of their additive or interactive effects is limited, particularly over larger spatial extents and longer timescales. To address these deficiencies, we created a dataset of land-use changes over 75 years, documenting the loss of over half (>3000 km2) the semi-natural grassland of Great Britain. Pairing this dataset with climate change data, we tested for relationships to distribution changes in birds, butterflies, macromoths, and plants (n = 1192 species total). We show that individual or additive effects of climate warming and land conversion unambiguously increased persistence probability for 40% of species, and decreased it for 12%, and these effects were reflected in both range contractions and expansions. Interactive effects were relatively rare, being detected in less than 1 in 5 species, and their overall effect on extinction risk was often weak. Such individualistic responses emphasise the importance of including species-level information in policies targeting biodiversity and climate adaptation.
Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects
Authors: Groh Janos , Abdelwahab Tassnim , Kattimani Yogita , Hörner Michaela , Loserth Silke , Gudi Viktoria , Adalbert Robert , Imdahl Fabian , Saliba Antoine-Emmanuel , Coleman Michael , Stangel Martin , Simons Mikael , Martini Rudolf
Published: October 2023

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
Authors: Wang Dongmei , Sun Tao , Xia Yuan , Zhao Zhe , Sheng Xue , Li Shuying , Ma Yuechan , Li Mingying , Su Xiuhua , Zhang Fan , Li Peng , Ma Daoxin , Ye Jingjing , Lu Fei , Ji Chunyan
Published: October 2023

CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Authors: Tschuck Juliane , Theilacker Lea , Rothenaigner Ina , Weiß Stefanie A. I. , Akdogan Banu , Lam Van Thanh , Müller Constanze , Graf Roman , Brandner Stefanie , Pütz Christian , Rieder Tamara , Schmitt-Kopplin Philippe , Vincendeau Michelle , Zischka Hans , Schorpp Kenji , Hadian Kamyar
Published: October 2023

Ferroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. Recent research has identified many regulators that induce or inhibit ferroptosis; yet, many regulatory processes and networks remain to be elucidated. In this study, we performed a chemical genetics screen using small molecules with known mode of action and identified two agonists of the nuclear receptor Farnesoid X Receptor (FXR) that suppress ferroptosis, but not apoptosis or necroptosis. We demonstrate that in liver cells with high FXR levels, knockout or inhibition of FXR sensitized cells to ferroptotic cell death, whereas activation of FXR by bile acids inhibited ferroptosis. Furthermore, FXR inhibited ferroptosis in ex vivo mouse hepatocytes and human hepatocytes differentiated from induced pluripotent stem cells. Activation of FXR significantly reduced lipid peroxidation by upregulating the ferroptosis gatekeepers GPX4, FSP1, PPARα, SCD1, and ACSL3. Together, we report that FXR coordinates the expression of ferroptosis-inhibitory regulators to reduce lipid peroxidation, thereby acting as a guardian of ferroptosis.
An autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer
Authors: Yan Jiaqi , Ma Xiaodong , Liang Danna , Ran Meixin , Zheng Dongdong , Chen Xiaodong , Zhou Shichong , Sun Weijian , Shen Xian , Zhang Hongbo
Published: October 2023

Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca2+ under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca2+ to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca2+ homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation.
Phylogenetic evidence reveals early Kra-Dai divergence and dispersal in the late Holocene
Authors: Tao Yuxin , Wei Yuancheng , Ge Jiaqi , Pan Yan , Wang Wenmin , Bi Qianqi , Sheng Pengfei , Fu Changzhong , Pan Wuyun , Jin Li , Zheng Hong-Xiang , Zhang Menghan
Published: October 2023

Studying language evolution brings a crucial perspective to bear on questions of human prehistory. As the most linguistically diverse region on earth, East and Southeast Asia have witnessed extensive sociocultural and ethnic contacts among different language communities. Especially, the Kra-Dai language family exhibits tremendous socio-cultural importance in these regions. Due to limited historical accounts, however, there are several controversies on their linguistic relatedness, ambiguities regarding the divergence time, and uncertainties on the dispersal patterns. To address these issues, here we apply Bayesian phylogenetic methods to analyze the largest lexical dataset containing 646 cognate sets compiled for 100 Kra-Dai languages. Our dated phylogenetic tree showed their initial divergence occurring approximately 4000 years BP. Phylogeographic results supported the early Kra-Dai language dispersal from the Guangxi-Guangdong area of South China towards Mainland Southeast Asia. Coupled with genetic, archaeological, paleoecologic, and paleoclimatic data, we demonstrated that the Kra-Dai language diversification could have coincided with their demic diffusion and agricultural spread shaped by the global climate change in the late Holocene. The interdisciplinary alignments shed light on reconstructing the prehistory of Kra-Dai languages and provide an indispensable piece of the puzzle for further studying prehistoric human activities in East and Southeast Asia.