bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin‐7 improves the fitness of regulatory T cells for adoptive transfer
Authors: Cosorich Ilaria , Filoni Jessica , Di Dedda Carla , Ferrari Arianna , Jofra Tatiana , Cesarano Susanna , Bonini Chiara , Piemonti Lorenzo , Monti Paolo
Published: September 2023

Adoptive regulatory T‐cell (Treg) transfer has emerged as a promising therapeutic strategy for regulating immune responses in organ transplantation, graft versus host disease, and autoimmunity, including Type 1 diabetes. Traditionally, Treg for adoptive therapy have been sorted and expanded in vitro using high doses of IL‐2, demonstrating stability and suppressive capabilities. However, limitations in their long‐term survival post‐infusion into patients have been observed. To address this challenge, we investigated a novel expansion protocol incorporating interleukin‐7 (IL‐7) alongside the traditional method utilizing IL‐2 (referred to as IL‐7 method, IL‐7M). Our study revealed that naïve Treg express significant levels of CD127 and display robust responsiveness to IL‐7, characterized by STAT‐5 phosphorylation. Expanding naïve Treg with the IL‐7M protocol led to a substantial enrichment of CD45RA+CD62L+CD95+ Treg but showing a reduction in the final cell yield and suppressive function. Moreover, Treg expanded with the IL‐7M exhibited preserved telomere length and demonstrated enhanced resistance to cytokine withdrawal and fas‐mediated apoptosis. When transferred into NSG mice IL‐7M‐Treg persisted longer and reduced the expansion of T cells, but did not significantly reduce the severity of xenoGvHD. In conclusion, our data demonstrate the feasibility of expanding naïve Treg in the presence of IL‐7 to generate a Treg product enriched in poorly differentiated CD45RA+ cells with enhanced survival capabilities.
Haptoglobin is an independent marker for disease severity and risk for metabolic complications in hidradenitis suppurativa: A prospective study
Authors: Abu Rached N. , Gambichler T. , Ocker L. , Skrygan M. , Seifert C. , Scheel C. H. , Stockfleth E. , Bechara F. G.
Published: September 2023

Background

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is highly correlated with obesity. Haptoglobin serum levels have recently been recognized as an important biomarker linking obesity with chronic inflammation.

Objective

To compare haptoglobin with previously proposed serum biomarkers for the determination of disease severity in HS patients. For this purpose, disease severity of HS patients was determined by a panel of clinical scores as well as several risk factors, such as weight and smoking habits.

Methods

A prospective, diagnostic accuracy study was performed at the International Centre for Hidradenitis suppurativa/Acne inversa Bochum (ICH). The study included a total of 263 patients, including 131 who had a confirmed diagnosis of HS in Hurley I (n = 16), II (n = 56) and III (n = 59) HS, and 132 healthy controls. The main outcome was to identify serological inflammatory markers for HS disease severity [severe (III) vs. moderate/mild (II/I)] as assessed by Hurley classification.

Results

The serum levels of acute phase proteins haptoglobin and CRP, as well as the number of neutrophils in peripheral blood, number of monocytes, the systemic immune‐inflammation index and the pan‐immune‐inflammatory value correlated with disease severity according to established clinical scores (mHSS, SAHS, Hurley, DLQI). HS patients had significantly higher haptologlobin levels compared to healthy controls. Logistic regression analysis revealed haptoglobin as the only independent marker predicting severe HS.

Conclusion

In this prospective study, we discovered that the serum levels of the acute phase protein haptoglobin levels serve as an independent marker of disease severity in HS. While this presents the first study in the context of HS. Thus, the present data not only yield a highly promising serum marker to be further validated.
Dynamic optical coherence tomography of chronic venous ulcers
Authors: Vélez González Jennifer Jahel , Berger Maximilian , Schiele Stefan , Rubeck Anna , Müller Gernot , Welzel Julia , Schuh Sandra
Published: September 2023

Background

Chronic ulcers, especially venous leg ulcers, are a major burden on the healthcare system. To date there are only few non‐invasive established procedures for evaluation of blood perfusion in wounds. Dynamic optical coherence tomography (D‐OCT) provides images of the skin's superficial vascularisation.

Objectives

This study aims to investigate if and how the D‐OCT measurement of chronic wounds can provide new information about the vascularisation during the healing process.

Methods

We examined 16 venous ulcers over 16 weeks and evaluated the vessel morphology and density using D‐OCT at the wound bed, borders, two centimetres adjacent to the wound und at non‐ulcerated skin on the contralateral leg.

Results

In D‐OCT scans clumps were unique and the most common vessel type in the wound area of venous ulcers, whereas lines and serpiginous vessels were the most common in non‐ulcerated skin. At the wound border mottle and cluster patterns occurred more frequently. Healthy skin showed a significant increase of mesh pattern. Vessel density significantly increased at the wound area compared to non‐ulcerated skin. During the healing process the wound border showed the most vascular changes while only an increase in curves was observed in the wound centre. Non‐healing wounds had fewer dots and blobs at the borders, fewer dots, coils, clumps, lines and serpiginous vessels at the centre and fewer dots in adjacent skin. Temperature analysis showed higher temperatures in non‐ulcerated skin, followed by the wound margin and centre. Non‐healing wounds showed the lowest temperatures in the wound centre.

Conclusions

These results highlight the non‐invasive use of D‐OCT for the examination and monitoring of wound healing in chronic venous ulcers. D‐OCT imaging of blood vessels may offer the potential to detect disorders of wound healing at an early stage, differentiate ulcers of different genesis and to tailor more individualized, patient‐oriented therapy.
Real‐world clinical, psychosocial and economic burden of atopic dermatitis: Results from a multicountry study
Authors: Eyerich Kilian , Gooderham Melinda J. , Silvestre Juan Francisco , Shumack Stephen P. , Mendes‐Bastos Pedro , Aoki Valeria , Ortoncelli Michela , Silverberg Jonathan I. , Teixeira Henrique D. , Chen Shirley H. , Calimlim Brian M. , Takemoto Shunya , Sancho Cristina , Fritz Björn , Irvine Alan D.
Published: September 2023

Background

Atopic dermatitis (AD), a relapsing, inflammatory skin disease, is associated with pruritus that can negatively affect patients' quality of life. Understanding the burden of AD is critical for informing and tailoring treatment and disease management to improve patient outcomes. This study characterized global treatment patterns and the clinical, psychosocial and economic burden of moderate‐to‐severe AD.

Methods

MEASURE‐AD was a cross‐sectional 28‐country study in patients with physician‐confirmed moderate‐to‐severe AD who were either receiving or eligible for systemic therapy for AD. Patients ≥12 years were enrolled between December 2019 and December 2020 while attending routine office or clinic visit. Primary outcomes included Worst Pruritus Numeric Rating Scale (WP‐NRS; range: 0–10) and Dermatology Life Quality Index (DLQI; range: 0–30) and Children's DLQI (CDLQI; range: 0–30). Secondary outcomes included physician‐ and patient‐reported clinical, psychosocial and economic burden.

Results

Of the 1591 patients enrolled, 1558 (1434 adults and 124 adolescents) fulfilled all patient selection criteria and were included in this analysis. Almost all patients (98.4%) in the total population were using AD medications and more than half (56%) were receiving systemic medication (15% systemic monotherapy). The most used systemic therapies were dupilumab (56.3%), systemic glucocorticoids (18.1%) and methotrexate (16.2%). Mean WP‐NRS was 5.3 in the total population, and most patients (≥55%) reported moderate‐to‐severe pruritus (WP‐NRS ≥4). Mean DLQI was 10.8 and mean CDLQI was 9.6. Secondary endpoints demonstrated substantial clinical, psychosocial, and economic burden of disease. Subgroup analysis demonstrated that patients receiving systemic therapy had lower disease burden than those not taking systemic medications.

Conclusions

While systemic therapy lowers overall disease burden, patients with moderate‐to‐severe AD continue to have substantial multidimensional disease burden and uncontrolled disease. Overall, there is a need for effective disease management, including effective treatments that improve patients' psychosocial outcomes and reduce the economic burden of AD.
Freshness prediction of modified atmosphere packaging lamb meat based on digital images from mobile portable devices
Authors: Jin Peilin , Li Zhigang , Zhang Xiaoshuan
Published: September 2023

This study aimed to quickly assess lamb meat freshness using smartphones under various modified atmosphere packaging and storage times (0–10 days). Lamb meat images were collected across different periods and packaging types (50% O2 + 40% CO2 + 10% N2; 70% O2 + 20% CO2 + 10% N2; air). Key color features were extracted, and significant differences in five color features were identified. Three distinct color feature combinations were chosen for models: support vector regression (SVR), genetic algorithm‐back propagation (GA‐BP) neural network, and convolutional neural network (CNN). Results showed SVR models with varied color feature inputs outperformed BP and CNN models. The SVR model with 12 input features yielded the best results, enabling effective spoilage level analysis of lamb meat under different storage times. This work establishes a foundation for future smartphone app development, utilizing Raspberry Pi hardware to evaluate lamb meat freshness under diverse storage conditions.

Practical applications

This study introduces a cell phone‐based method to rapidly determine lamb spoilage in air conditioning packages during different storage times. Using cell phone images, we collected data on lamb samples stored for 0–10 days under three packaging conditions. We extracted significant color features and selected three combinations as inputs for prediction models: SVR, GA‐BP neural network, and CNN. The SVR model with 12 feature values demonstrated the best performance. This research lays the foundation for a cell phone application based on Raspberry Pi hardware, enabling users to assess lamb freshness in various storage conditions. The potential benefits include efficient quality control in the food industry, increased consumer confidence, and improved preservation of lamb products through optimized storage and packaging. Overall, this study contributes to food quality evaluation and provides practical applications for professionals and consumers.
Processing and preservation of apple juice by pulsed electric fields combined with cinnamon essential oils: Exploring the effect of synergism
Authors: Akdemir Evrendilek Gulsun , Karaoğuz Turgut Bengi
Published: September 2023

Apple juice samples were treated by pulsed electric field (PEF) alone and in combination with cinnamon essential oils (CEO) at 0.0005, 0.003, and 0.06 μL mL−1 concentrations as a function of treatment time. Results revealed 11 different compounds with the highest concentrations of 44.79% 3‐propenal 3‐phenyl, 34.98% trans‐cinnamaldehyde, and 10.18% 4‐propenal 3‐phenyl in CEO. pH and total soluble solids of the apple juice samples significantly decreased; whereas total phenolic substance content of the samples significantly increased by added CEO. The same process parameters caused 3.26 ± 0.19 and 3.83 ± 0.16 log reductions on TAMB and TMY, revealing no detectable numbers after PEF treatment. Similarly, maximum 5.13 and 3.87 log reductions on Escherichia coli O157:H7 and Listeria monocytogenes were obtained on 0.06 μL mL−1 CEO added samples treated after 604 μs. Moreover, increased CEO concentration, when treatment time was constant, caused significantly more microbial inactivation. Increase in treatment time resulted in an incline on ΔH of the samples. Response optimization revealed that 604 μs treatment time and 0.06 μL mL−1 concentration were the optimal treatment parameters with 0.63 composite desirability.
Investigating the effects of whole genome duplication on phenotypic plasticity: implications for the invasion success of giant goldenrod Solidago gigantea
Authors: Walczyk Angela M. , Hersch‐Green Erika I.
Published: September 2023

Polyploidy commonly occurs in invasive species, and phenotypic plasticity (PP, the ability to alter one's phenotype in different environments) is predicted to be enhanced in polyploids and to contribute to their invasive success. However, empirical support that increased PP is frequent in polyploids and/or confers invasive success is limited. Here, we investigated if polyploids are more pre‐adapted to become invasive than diploids via the scaling of trait values and PP with ploidy level, and if post‐introduction selection has led to a divergence in trait values and PP responses between native‐ and non‐native cytotypes. We grew diploid, tetraploid (from both native North American and non‐native European ranges), and hexaploid Solidago gigantea in pots outside with low, medium, and high soil nitrogen and phosphorus (NP) amendments, and measured traits related to growth, asexual reproduction, physiology, and insects/pathogen resistance. Overall, we found little evidence to suggest that polyploidy and post‐introduction selection shaped mean trait and PP responses. When we compared diploids to tetraploids (as their introduction into Europe was more likely than hexaploids) we found that tetraploids had greater pathogen resistance, photosynthetic capacities, and water‐use efficiencies and generally performed better under NP enrichments. Furthermore, tetraploids invested more into roots than shoots in low NP and more into shoots than roots in high NP, and this resource strategy is beneficial under variable NP conditions. Lastly, native tetraploids exhibited greater plasticity in biomass accumulation, clonal‐ramet production, and water‐use efficiency. Cumulatively, tetraploid S. gigantea possesses traits that might have predisposed and enabled them to become successful invaders. Our findings highlight that trait expression and invasive species dynamics are nuanced, while also providing insight into the invasion success and cyto‐geographic patterning of S. gigantea that can be broadly applied to other invasive species with polyploid complexes.
Hand‐blink reflex modulation: The role of primary emotions and attachment dimensions
Authors: Mercante Beniamina , Uccula Arcangelo , Secchi Eleonora , Puggioni Graziella , Loi Nicola , Enrico Paolo , Deriu Franca
Published: September 2023

The hand‐blink reflex (HBR) is a subcortical response elicited by the electrical stimulation of the median nerve. HBR magnitude is enhanced when the stimulated hand is close to the face and is modulated by high‐level structures according to the perceived threat magnitude. Psychological factors may contribute to threat evaluation and possibly to HBR amplitude modulation. In this study, we assessed distinctively emotional and relational aspects of personality and evaluated their associations with the HBR response, or lack thereof, in healthy subjects. Seventy‐one volunteers filled the Experiences in Close Relationships Scale, the Affective Neuroscience Personality Scales, and the State–Trait Anxiety Inventory Form Y questionnaires and underwent HBR recording. We found that the HBR could be evoked only in 50.7% of all subjects (responders). Non‐responders subjects showed higher scores in the avoidance dimension (p = .005), and lower scores in the care dimension (p = .008), compared with responders. In responders, regression analysis showed a negative association of HBR amplitude (difference in near vs. far responses) with anger dimension and a positive association with state anxiety (R2 = 0.239). A positive association also emerged with HBR latency and fear dimension (R2 = 0.419). We conclude that primary emotional and relational factors may play an important role in the modulation of brainstem circuits mediating the HBR response. Our results may also contribute to the question about the absence of the HBR in about half of the subjects since high‐level cognitive processes seem to play an important role in the differentiation between responder and non‐responder.
The implementation of social protection in a conservative African welfare regime: The values and beliefs of local state officials in Botswana
Authors: Seekings Jeremy
Published: September 2023

Social protection has grown in importance in framing the relationship between citizens and states across much of Africa. Botswana's conservative welfare regime relies heavily on local officials – many of whom are trained social workers – to exercise discretion in assessing the needs of poor people and registering them on social protection programmes. Interviews with local officials reveal that they attribute poverty and destitution primarily to the deficient attitudes and behaviour of poor people. These are in turn seen as the consequence of social protection policies that disempower people by fostering ‘dependence’ on state provision. Local officials prefer programmes that ‘empower’ poor people. Whilst they recognise that the state has responsibilities towards the poor, they implement policies that reinforce and reproduce the status of poor citizens as often undeserving claimants on public charity.
Natural alleles of Mediator subunit genes modulate plant height in chickpea
Authors: Malik Naveen , Basu Udita , Srivastava Rishi , Daware Anurag , Ranjan Rajeev , Sharma Akash , Thakro Virevol , Mohanty Jitendra K. , Jha Uday Chand , Tripathi Shailesh , Tyagi Akhilesh K. , Parida Swarup K.
Published: September 2023

Plant height (PH) is an important plant architectural trait targeted during Green Revolution to enhance crop yields. Identification of genes and natural alleles governing plant height without compromising agronomic performance can fill the lacuna of knowledge connecting ideal plant architecture with maximum achievable yield in chickpea. Through coherent strategy involving genome‐wide association study, QTL/fine mapping, map‐based cloning, molecular haplotyping, and downstream functional genomics, the current study identified two Mediator subunit genes namely, CaMED23 and CaMED5b and their derived natural alleles/haplotypes underlying the major QTLs and trans‐acting eQTLs regulating plant height in chickpea. Differential accumulation of haplotype‐specific transcripts of these two Mediator genes in corresponding haplotype‐introgressed near‐isogenic lines (NILs) correlates negatively with the plant height trait. Quantitative as well as qualitative estimation based on histology, scanning electron microscopy, and histochemical assay unraveled the reduced lengths and cell sizes of internodes along with compromised lignin levels in dwarf/semi‐dwarf chickpea NILs introgressed with superior CaMED23 and CaMED5b gene haplotypes. This observation, supported by global transcriptome profiling‐based diminished expression of various phenylpropanoid pathway genes upstream of lignin biosynthesis in dwarf/semi‐dwarf NILs, essentially links plant height with lignin accumulation. The identified molecular signatures in the Mediator subunit genes can be efficiently utilized to develop desirable dwarf/semi‐dwarf‐type chickpea cultivars without affecting their yield per plant via modulating lignin/phenylpropanoid biosynthesis.
Foreign influence: The international transmission of gender equality
Authors: Davis C. Austin , Poole Jennifer P.
Published: September 2023

Anecdotal evidence for several developing countries suggests that foreign direct investment and multinational enterprises (MNEs) may be an important conduit of cultural exchange. Recent work in economics has explored the role that MNEs play in transferring gender equality around the globe, but with mixed results. In this paper, we consider the implications of increased foreign direct investment in Brazil on the transmission of high‐quality gender policy and practice. In particular, we investigate whether workers with experience at multinational firms, now employed in domestic firms with no foreign influence, help to change gender‐specific outcomes at their Brazilian companies. We next ask whether it matters from where the foreign direct investment originates—that is, do workers with experience in MNEs with headquarters in relatively gender‐equal countries transfer best practices toward women better than do workers with experience in MNEs from relatively more gender‐unequal countries? Increasing the share of workers with MNE experience modestly improves the gender earnings gap in some specifications. Additionally, workers in management positions offer the strongest positive contributions to closing gender gaps. However, despite the many theoretical reasons and suggestive empirical evidence from previous literature to expect differential implications across FDI‐source countries, our data fail to support this notion.
Blood donor genotyping for prediction of blood group antigens: Results from 5 years' experience (2017–2022)
Authors: Rieneck Klaus , Krog Grethe Risum , Clausen Frederik Banch , Egeberg Hother Christoffer , Dziegiel Morten Hanefeld
Published: September 2023

Background and Objectives

For 5 years, routine genotyping has been performed for selected blood groups of blood donors in the Copenhagen Capital Region, Denmark. The result is summarized in the following.

Materials and Methods

Genotyping was carried out by an external service provider using the competitive allele specific PCR (KASP) technology. The genotypes were returned to the blood bank and translated into phenotypes by a proprietary IT application.

Results

In total, 65 alleles from 16 blood group systems (ABO, MNS, Rh, Lutheran, Kell, Duffy, Kidd, Diego, Yt, Dombrock, Colton, Landsteiner‐Wiener, Cromer, Knops, Vel, secretor status) and the HPA1, HPA5 and HPA15 antigens were interrogated. After translation, phenotypes were imported into the laboratory information management system of the blood bank. The results from 31,538 genotyped blood donors were used to calculate the allele frequencies for a Danish blood donor population. ABO genotyping was done for sample ID purposes. Determination of the 1061delC single nucleotide polymorphism (SNP) (NM_020469.2), most frequently characteristic of ABO*A2, was validated against a series of 1287 samples with Dolichos biflorus lectin determination of the A1 phenotype.

Conclusion

We report allele frequencies and phenotype frequencies for 16 blood groups from a total of 31,538 genotyped blood donors. Blood products were supplied from a total of 64,312 active blood donors, and of these active blood donors 25,396 (39.5%) were genotyped. These donors represent a valuable resource for patient treatment. This genotyping has enabled the provision of rare genotyped donor blood for patients with alloantibodies and rare reagent cells for serology.
Degree zero Gromov–Witten invariants for smooth curves
Authors: Yang Di
Published: September 2023

For a smooth projective curve, we derive a closed formula for the generating series of its Gromov–Witten invariants in genus and degree zero. It is known that the calculation of these invariants can be reduced to that of the and integrals on the moduli space of stable algebraic curves. The closed formula for the integrals is given by the conjecture, proved by Faber and Pandharipande. We compute in this paper the integrals via solving the degree zero limit of the loop equation associated to the complex projective line.
An Unusual Fossiliferous Site in the Romualdo Formation in the Socorro Basin (Northeast Brazil)
Authors: Barros Olga Alcântara , Saraiva Antônio Álamo Feitosa , Oliveira Juliana Trindade Marques de , Filho Edilson Bezerra Dos Santos , Alves Ana Maria de Souza , Lima Flaviana Jorge de , Bantim Renan Alfredo Machado
Published: September 2023

The Santana Group, from the base to the top, comprises the Barbalha, Crato, Ipubi, and Romualdo formations. Calcareous concretions from the Romualdo Formation are found in the Araripe Basin, but the geographic extension of this sequence has evidence in the Socorro Basin on the border of the state of Pernambuco; however, these areas outside of the Araripe Basin have rarely been investigated. The purpose of this research was to carry out a data survey of fossils collected in the Romualdo Formation from the Socorro/Santo Ignácio Basin area that were found in the northeastern portion of Ouricuri municipality in the state of Pernambuco; a new fossiliferous site, known as the Cara Branca site, is reported. Samples were collected from the surface and often in the off-season. This area is cleared by tractors for planting, either exposing fossils or moving some of the fossils. This disturbance reinforces the need for fossil rescues and excavations in this area, where weathering, agricultural machinery, and erosion can damage the fossil record. According to the initial paleontological sampling, the obtained taphonomic information pointed to rapid burial, and the degrees of disarticulation observed in some specimens indicated that disarticulation occurred through necrolysis.
Identificación del paisaje cultural en un barrio histórico a través de sus jardines urbanos: el caso de Barrio República, Santiago de Chile
Authors: Alvarado Castro Paulina , Ramírez Scheel Alfonsina , Núñez Escudero Macarena
Published: September 2023

Los jardines urbanos en barrios con historia aportan a su imagen patrimonial, relevando sus atributos. En Barrio República, ubicado en Santiago de Chile, surge la necesidad de encausar la idea de que estos espacios, ubicados en las calles, pasajes y avenidas, sean identificados como paisajes culturales por sus valores históricos y sociales, que hablan de pertenencia y vinculación actual urbana con sus residentes y vecinos/as. Todo ello, con base en la comprensión del concepto según distintos autores, un análisis historiográfico y el desarrollo de entrevistas realizadas a lo largo del proceso, que dan cuenta de la importancia de los jardines en las diversas formas de vida, antiguas y actuales, permeando en las relaciones sociales y manteniendo así un espíritu de comunidad que las une y fortalece.
Inertia Modulated Meta-Structure With Time-Varying Inertia Amplification
Authors: Gao Hao , Zhu Junzhe , Qu Yegao , Meng Guang
Published: September 2023

In this work, a new inertia modulated meta-structure is proposed to enable time-dependent inertia parameters, and thereby realize non-reciprocal wave propagation via spatiotemporal modulation. The designed cell structure is composed of an oscillatory disk and a mass that slides in a guide embedded in the disk frictionlessly with prescribed motion. Effective moment of inertia and damping coefficients of the rocking motion of the cell structure are rendered time-dependent due to the inertia and Coriolis forces of the periodically sliding mass, which allows us to implement the expected spatiotemporal modulation upon a super-cell. Non-reciprocal propagation behavior of the proposed meta-structure is verified via the theoretical solution of the dispersion relation as well as the dynamic response of a finite array. Effects of modulation parameters, including the frequency, amplitude, and phase, on the unidirectional propagation characteristic are thoroughly investigated.
How thresholding in segmentation affects the regression performance of the linear model
Authors: Kuberski Stephan R. , Gafos Adamantios I.
Published: September 2023

Evaluating any model underlying the control of speech requires segmenting the continuous flow of speech effectors into sequences of movements. A virtually universal practice in this segmentation is to use a velocity-based threshold which identifies a movement onset or offset as the time at which the velocity of the relevant effector breaches some threshold percentage of the maximal velocity. Depending on the threshold choice, more or less of the movement's trajectory is left in for model regression. This paper makes explicit how the choice of this threshold modulates the regression performance of a dynamical model hypothesized to govern speech movements.
Destruction and regrowth of lithospheric mantle beneath large igneous provinces
Authors: Stephenson Simon N. , Ball Patrick W. , Richards Fred D.
Published: September 2023

Large igneous provinces (LIPs) are formed by enormous (i.e., frequently >10
6
km
3
) but short-lived magmatic events that have profound effects upon global geodynamic, tectonic, and environmental processes. Lithospheric structure is known to modulate mantle melting, yet its evolution during and after such dramatic periods of magmatism is poorly constrained. Using geochemical and seismological observations, we find that magmatism is associated with thin (i.e., ≲80 km) lithosphere and we reveal a striking positive correlation between the thickness of modern-day lithosphere beneath LIPs and time since eruption. Oceanic lithosphere rethickens to 125 km, while continental regions reach >190 km. Our results point to systematic destruction and subsequent regrowth of lithospheric mantle during and after LIP emplacement and recratonization of the continents following eruption. These insights have implications for the stability, age, and composition of ancient, thick, and chemically distinct lithospheric roots, the distribution of economic resources, and emissions of chemical species that force catastrophic environmental change.
Topological packing statistics of living and nonliving matter
Authors: Skinner Dominic J. , Jeckel Hannah , Martin Adam C. , Drescher Knut , Dunkel Jörn
Published: September 2023

Complex disordered matter is of central importance to a wide range of disciplines, from bacterial colonies and embryonic tissues in biology to foams and granular media in materials science to stellar configurations in astrophysics. Because of the vast differences in composition and scale, comparing structural features across such disparate systems remains challenging. Here, by using the statistical properties of Delaunay tessellations, we introduce a mathematical framework for measuring topological distances between general three-dimensional point clouds. The resulting system-agnostic metric reveals subtle structural differences between bacterial biofilms as well as between zebrafish brain regions, and it recovers temporal ordering of embryonic development. We apply the metric to construct a universal topological atlas encompassing bacterial biofilms, snowflake yeast, plant shoots, zebrafish brain matter, organoids, and embryonic tissues as well as foams, colloidal packings, glassy materials, and stellar configurations. Living systems localize within a bounded island-like region of the atlas, reflecting that biological growth mechanisms result in characteristic topological properties.
Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet
Authors: Iuso Domenico , Garcia-Saez Isabel , Couté Yohann , Yamaryo-Botté Yoshiki , Boeri Erba Elisabetta , Adrait Annie , Zeaiter Nour , Tokarska-Schlattner Malgorzata , Jilkova Zuzana Macek , Boussouar Fayçal , Barral Sophie , Signor Luca , Couturier Karine , Hajmirza Azadeh , Chuffart Florent , Bourova-Flin Ekaterina , Vitte Anne-Laure , Bargier Lisa , Puthier Denis , Decaens Thomas , Rousseaux Sophie , Botté Cyrille , Schlattner Uwe , Petosa Carlo , Khochbin Saadi
Published: September 2023

The synthesis of fatty acids from acetyl–coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3′ phosphate. We report that
Nme2
knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells, NME2 mediates a gene transcriptional response to HFD leading to the repression of fatty acid accumulation and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling AcCoA usage between the competing paths of histone acetylation and fatty acid synthesis.
Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases
Authors: Herman Jonathan D. , Atyeo Caroline , Zur Yonatan , Cook Claire E. , Patel Naomi J. , Vanni Kathleen M. , Kowalski Emily N. , Qian Grace , Srivatsan Shruthi , Shadick Nancy A. , Rao Deepak A. , Kellman Benjamin , Mann Colin J. , Lauffenburger Douglas , Wallace Zachary S. , Sparks Jeffrey A. , Alter Galit
Published: September 2023

Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2– or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti–SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs.
Stem-like CD4
+
T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis
Authors: Sato Yuki , Jain Abhinav , Ohtsuki Shozo , Okuyama Hirohisa , Sturmlechner Ines , Takashima Yoshinori , Le Kevin-Phu C. , Bois Melanie C. , Berry Gerald J. , Warrington Kenneth J. , Goronzy Jörg J. , Weyand Cornelia M.
Published: September 2023

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4
+
T cell population with stem cell–like features. CD4
+
T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)
+
cytotoxic T cells and B cell lymphoma 6 (BCL6)
+
T follicular helper-like cells. TCF1
hi
CD4
+
T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1
hi
CD4
+
T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4
+
T cells instead of only effector T cells.
Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas
Authors: Peruzzi Pierpaolo , Dominas Christine , Fell Geoffrey , Bernstock Joshua D. , Blitz Sarah , Mazzetti Debora , Zdioruk Mykola , Dawood Hassan Y. , Triggs Daniel V. , Ahn Sebastian W. , Bhagavatula Sharath K. , Davidson Shawn M. , Tatarova Zuzana , Pannell Michael , Truman Kyla , Ball Anna , Gold Maxwell P. , Pister Veronika , Fraenkel Ernest , Chiocca E. Antonio , Ligon Keith L. , Wen Patrick Y. , Jonas Oliver
Published: September 2023

The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ. IMDs are integrated into surgical practice during tumor resection and remain in situ only for the duration of the otherwise standard operation (2 to 3 hours). None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Analysis of the specimens provided preliminary evidence of the robustness of the readout, compatibility with a wide array of techniques for molecular tissue interrogation, and promising similarities with the available observed clinical-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMDs allows characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor, and without affecting the standard surgical workflow.
Prenatal exposure to RSV season influences first-year risk of RSV lower respiratory illness and RSV-specific immune responses assessed at birth
Authors: Nenna Raffaella , Stern Debra A. , Carr Tara F. , Spangenberg Amber , Wright Anne L. , Martinez Fernando D. , Halonen Marilyn
Published: September 2023

Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children’s Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV.

IMPORTANCE

Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring
in utero
.
Treponema pallidum
PCR screening at mucosal sites of asymptomatic men who have sex with men taking HIV pre-exposure prophylaxis
Authors: Aung Ei T. , Fairley Christopher K. , Williamson Deborah A. , Azzato Francesca , Wigan Rebecca , Tran Julien , Buchanan Andrew , Schmidt Tina , Chow Eric P. F. , Chen Marcus Y.
Published: September 2023

Early detection and treatment of syphilis will reduce the infectious period and transmission. We aimed to determine whether screening men who have sex with men (MSM) taking HIV pre-exposure prophylaxis (PrEP) for syphilis using
Treponema pallidum
polymerase chain reaction (PCR) could detect syphilis before the appearance of syphilis antibodies in serology. MSM attending 3-monthly PrEP clinic visits in Melbourne, Australia, were screened with a PCR assay targeting the
pol
A gene of
T. pallidum
from an anal swab and an oral rinse between November 2019 and March 2020. Participants were serologically screened for syphilis using chemiluminescence immunoassay. A total of 309 asymptomatic participants provided an anal swab and oral rinse sample for
T. pallidum
PCR screening. Two syphilis cases (0.6%) were detected: one man had a positive serology only; another man had
T. pallidum
detected by PCR from an anal swab and a positive serology. PCR positivity was 0.3% (
n
= 1) for anal swabs and 0% (
n
= 0) for oral rinse. In this study,
T. pallidum
PCR screening at routine PrEP clinic visits did not identify additional cases of early syphilis over serological screening performed at these visits.

IMPORTANCE

With the ongoing syphilis epidemic in men who have sex with men (MSM), we investigated the role of using
Treponema pallidum
polymerase chain reaction (PCR) testing at the oral cavity and anus in MSM taking pre-exposure prophylaxis for the early detection of syphilis. We evaluated whether the PCR tests from these mucosal sites can detect syphilis infection early, before the development of syphilis antibodies in serology. Our study found two syphilis cases among 309 MSM, and only one syphilis case had a positive anal PCR swab, although serology was positive. We conclude that additional PCR testing is likely to be expensive and would not be cost effective for individuals who regularly screen for syphilis. However, future studies with a larger sample size are required.
Global trends in incidence, death, burden and risk factors of early-onset cancer from 1990 to 2019
Authors: Zhao Jianhui , Xu Liying , Sun Jing , Song Mingyang , Wang Lijuan , Yuan Shuai , Zhu Yingshuang , Wan Zhengwei , Larsson Susanna , Tsilidis Konstantinos , Dunlop Malcolm , Campbell Harry , Rudan Igor , Song Peige , Theodoratou Evropi , Ding Kefeng , Li Xue
Published: September 2023

Objective

This study aimed to explore the global burden of early-onset cancer based on the Global Burden of Disease (GBD) 2019 study for 29 cancers worldwid.

Methods and analysis

Incidence, deaths, disability-adjusted life years (DALYs) and risk factors for 29 early-onset cancer groups were obtained from GBD.

Results

Global incidence of early-onset cancer increased by 79.1% and the number of early-onset cancer deaths increased by 27.7% between 1990 and 2019. Early-onset breast, tracheal, bronchus and lung, stomach and colorectal cancers showed the highest mortality and DALYs in 2019. Globally, the incidence rates of early-onset nasopharyngeal and prostate cancer showed the fastest increasing trend, whereas early-onset liver cancer showed the sharpest decrease. Early-onset colorectal cancers had high DALYs within the top five ranking for both men and women. High-middle and middle Sociodemographic Index (SDI) regions had the highest burden of early-onset cancer. The morbidity of early-onset cancer increased with the SDI, and the mortality rate decreased considerably when SDI increased from 0.7 to 1. The projections indicated that the global number of incidence and deaths of early-onset cancer would increase by 31% and 21% in 2030, respectively. Dietary risk factors (diet high in red meat, low in fruits, high in sodium and low in milk, etc), alcohol consumption and tobacco use are the main risk factors underlying early-onset cancers.

Conclusion

Early-onset cancer morbidity continues to increase worldwide with notable variances in mortality and DALYs between areas, countries, sex and cancer types. Encouraging a healthy lifestyle could reduce early-onset cancer disease burden.
Characterising meaningful patient and public involvement in the pharmaceutical industry research setting: a retrospective quality assessment
Authors: Dews Sally-Anne , Bassi Adit , Buckland Sean , Clements Lucy , Daley Rachel , Davies Angela , Evett Sophie , Howland Samantha , Kinloch Emma , Phillips Berkeley , Powell Gareth , Preston Jennifer , Sterniczuk Kamil , Bohm Natalie
Published: September 2023

Objectives

Patient and public involvement (PPI) in clinical research has a well-established infrastructure in the UK, and while there has been good progress within pharmaceutical-industry-sponsored research, further improvements are still needed. This review aims to share learnings from quality assessments of historical PPI projects within Pfizer UK to inform future projects and drive PPI progress in the pharmaceutical industry.

Design and setting

Internal assessments of Pfizer UK PPI projects were conducted to identify all relevant projects across the medicines development continuum between 2017 and 2021. Five sample projects were developed into case studies.

Outcome measure

Retrospective quality assessments were performed using the Patient Focused Medicines Development (PFMD) Patient Engagement Quality Guidance (PEQG) tool. Recommendations for improvement were developed.

Results

Retrospective case study analysis and quality framework assessment revealed benefits of PPI to both Pfizer UK and to external partners, as well as challenges and learnings to improve future practice. Recommendations for improvement based on these findings focused on processes and procedures for PPI, group dynamics and diversity for PPI activities, sharing of expertise, the importance of bidirectional and timely feedback, and the use of understandable language in materials.

Conclusions

PPI in medicines development is impactful and beneficial but is still being optimised in the pharmaceutical industry. Using the PFMD PEQG tool to define gaps, share learnings and devise recommendations for improvement helps to ensure that PPI is genuine and empowering, rather than tokenistic. Ultimately, these recommendations should be acted on to further embed PPI as an integral part of medicines development and health research within the pharmaceutical industry. This article includes a plain language summary in the supplement.