bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of CD7⁺CXCR3⁺ CAR T cells with long-term remission in R/R DLBCL
Authors: Bartolini Robin , Trueb Lionel , Daoudlarian Douglas , Joo Victor , Noto Alessandra , Stadelmann Raphaël , Gentner Bernhard , Fenwick Craig , Perreau Matthieu , Coukos Georges , Pantaleo Giuseppe , Arber Caroline , Obeid Michel
Published: December 2024

Background.

CAR T-cell therapy is the standard of care for R/R DLBCL, but more than half of patients fail to achieve long-term remission. Identification of cellular biomarkers in CAR T- cell infusion products (IPs) that predict complete remission beyond six months may guide the development of strategies to improve outcomes.

Methods.

IPs from 13 R/R DLBCL patients were analyzed using a 39-marker mass cytometry panel, comparing cell populations between long-term responders (R) and non-responders (NR). Both unsupervised and supervised analyses were performed. Longitudinal blood samples were analyzed for 30 days to track CAR T-cell subpopulation dynamics.

Results.

At a median follow-up of 13.5 months, median progression-free survival (PFS) was 13.3 months (95% CI: 9.7-24.3) in R (n=8) versus 3.5 months (95% CI: 0.5-5.4) in NR (n=5).

The HR for PFS was 56.67 (95% CI: 7.3-439.3; P=0.0001). A subset of CD3+CXCR3+CD7+CAR T-cells found in both CD4+and CD8+populations was significantly enriched in R and expressed higher levels of perforin, granzyme B, and NKG2D (restricted to CD8+). NR had more CXCR3+CD7+LAG3+CAR T-cells. CD3, CD7, CXCR3, and NKG2D cell surface levels were higher in R, whereas LAG3, Ki67, and CD71 were elevated in NR. A predictive cut-off ratio of CD3+CXCR3+CD7+LAG3+CAR+T-cells <0.83 and CD3+CXCR3+CD7+NKG2D+CAR+T-cells >1.034 yielded a predictive accuracy of 0.92. Serum CXCL9 and CXCL10 levels were not different between groups.

Conclusions.

Increased frequency of CAR T-cells expressing CD7, CXCR3 and NKG2D in R versus LAG3 and CD71 in NR emerged as strong correlates of therapeutic outcome.
Leveraging DNA methylation to create Epigenetic Biomarker Proxies that inform clinical care: A new framework for Precision Medicine
Authors: Carreras-Gallo Natàlia , Chen Qingwen , Balagué-Dobón Laura , Aparicio Andrea , Giosan Ilinca M. , Dargham Rita , Phelps Daniel , Guo Tao , Mendez Kevin M. , Chen Yulu , Carangan Athena , Vempaty Srikar , Hassouneh Sayf , McGeachie Michael , Mendez Tavis , Comite Florence , Suhre Karsten , Smith Ryan , Dwaraka Varun B. , Lasky-Su Jessica A.
Published: December 2024

The lack of accurate, cost-effective, and clinically relevant biomarkers remains a major barrier to incorporating omic data into clinical practice. Previous studies have shown that DNA methylation algorithms have utility as surrogate measures for selected proteins and metabolites. We expand upon this work by creating DNAm surrogates, termed epigenetic biomarker proxies (EBPs), across clinical laboratories, the metabolome, and the proteome. After screening >2,500 biomarkers, we trained and tested 1,694 EBP models and assessed their incident relationship with 12 chronic diseases and mortality, followed up to 15 years. We observe broad clinical relevance: 1) there are 1,292 and 4,863 FDR significant incident and prevalent associations, respectively; 2) most of these associations are replicated when looking at the lab-based counterpart, and > 62% of the shared associations have higher odds and hazard ratios to disease outcomes than their respective observed measurements; 3) EBPs of current clinical biochemistries detect deviations from normal with high sensitivity and specificity. Longitudinal EBPs also demonstrate significant changes corresponding to the changes observed in lab-based counterparts. Using two cohorts and > 30,000 individuals, we found that EBPs validate across healthy and sick populations. While further study is needed, these findings highlight the potential of implementing EBPs in a simple, low-cost, high-yield framework that benefits clinical medicine.
Computationally efficient meta-analysis of gene-based tests using summary statistics in large-scale genetic studies
Authors: Joseph Tyler , Mbatchou Joelle , Ghosh Arkopravo , Marcketta Anthony , Gillies Christopher , Tang Jing , Nakka Priyanka , Zhang Xinyuan , Kosmicki Jack , Sidore Carlo , Gurski Lauren ,   Regeneron Genetics Center, Ghoussaini Maya , Ferreira Manuel A.R. , Abecasis Gonçalo , Marchini Jonathan
Published: December 2024

Meta-analysis of gene-based tests using single variant summary statistics is a powerful strategy for associating genes with disease. However, current approaches require sharing the covariance matrix between variants for each study and trait of interest. For large-scale studies with many phenotypes, these matrices can be cumbersome to calculate, store, and share. To address this challenge, we present REMETA, an efficient tool for meta-analysis of gene-based tests. REMETA uses a single sparse covariance reference file per study that is rescaled for each phenotype using single variant summary statistics. We develop methods to apply REMETA to binary traits with case-control imbalance, and estimate allele frequencies, genotype counts and effect sizes of burden tests. We demonstrate the performance and advantages of our approach via meta-analysis of 5 traits in 469,376 samples in UK Biobank. The open-source REMETA software tools and framework will facilitate meta-analysis across large scale exome sequencing studies from diverse studies that cannot easily be brought together.
Efficient multi-phenotype genome-wide analysis identifies genetic associations for unsupervised deep-learning-derived high-dimensional brain imaging phenotypes
Authors: Guo Bohong , Xie Ziqian , He Wei , Islam Sheikh Muhammad Saiful , Gottlieb Assaf , Chen Han , Zhi Degui
Published: December 2024

Brain imaging is a high-content modality that offers dense insights into the structure and pathology of the brain. Existing genetic association studies of brain imaging, typically focusing on a number of individual image-derived phenotypes (IDPs), have successfully identified many genetic loci. Previously, we have created a 128-dimensional Unsupervised Deep learning derived Imaging Phenotypes (UDIPs), and identified multiple loci from single-phenotype genome-wide association studies (GWAS) for individual UDIP dimensions, using data from the UK Biobank (UKB). However, this approach may miss genetic associations where one single nucleotide polymorphism (SNP) is moderately associated with multiple UDIP dimensions. Here, we present Joint Analysis of multi-phenotype GWAS (JAGWAS), a new tool that can efficiently calculate multivariate association statistics using single-phenotype summary statistics for hundreds of phenotypes. When applied to UDIPs of T1 and T2 brain magnetic resonance imaging (MRI) on discovery and replication cohorts from the UKB, JAGWAS identified 195/168 independently replicated genomic loci for T1/T2, 6 times more than those from the single-phenotype GWAS. The replicated loci were mapped into 555/494 genes, and 217/188 genes overlapped with the expression quantitative trait loci (eQTL) of brain tissues. Gene enrichment analysis indicated that the genes mapped are closely related to neurobiological functions. Our results suggested that multi-phenotype GWAS is a powerful approach for genetic discovery using high-dimensional UDIPs.
Cost-utility analysis of COVID-19 vaccination strategies for endemic SARS-CoV-2 circulation in Canada
Authors: Miranda Rafael N. , Simmons Alison E. , Li Michael W.Z. , Gebretekle Gebremedhin B. , Xi Min , Salvadori Marina I. , Warshawsky Bryna , Wong Eva , Ximenes Raphael , Andrew Melissa K. , Sander Beate , Singh Davinder , Wilson Sarah , Tunis Matthew , Tuite Ashleigh R.
Published: December 2024

Background

With shifting epidemiology and changes in the vaccine funding landscape, resource use considerations for ongoing COVID-19 vaccination programs are increasingly important. We assessed the cost-effectiveness of COVID-19 vaccination programs, where eligibility is defined by combinations of age and chronic medical conditions, including a strategy similar to current Canadian recommendations, from the health system and societal perspectives.

Methods

We used a static, individual-based probabilistic model simulating medically attended COVID-19 in a population of 1 million people followed over a 15-month time period to estimate costs in 2023 Canadian dollars, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), discounted at 1.5%. COVID-19 epidemiology, vaccine characteristics, and costs were based on the most recently available data.

Results

Annual vaccination for adults aged 65 years and older consistently emerged as a cost-effective intervention, with ICERs less than $50,000 per QALY compared to no vaccination for a range of model assumptions. Adding a second dose for adults aged 65 years and older or expanding programs to include vaccination for younger age groups, including those at higher risk of COVID-19 due to chronic medical conditions, generally resulted in ICERs of greater than $50,000 per QALY. Shifting timing of vaccination programs to better align with periods of high COVID-19 case occurrence could result in biannual vaccination for those aged 65 and older being a cost-effective strategy.

Conclusions

COVID-19 vaccination programs may be cost-effective when focused on groups at higher risk of disease. Optimal timing of vaccination could improve the cost-effectiveness of various strategies.
Differentiation of Mesenchymal Stem/ Stromal Cells into CD45+ Macrophage-like Cells: Expanding Insights into MSC Plasticity
Authors: Rusch Robert M. , Mabuchi Yo , Morikawa Satoru , Ogawa Yoko , Shimmura Shigeto
Published: December 2024

Mesenchymal stem/stromal cells (MSCs) are notable for their differentiation potential and immunomodulatory properties. They share several features with macrophages that are also similar to those of fibrocytes. This study aimed to investigate the relationship between MSCs, fibrocytes, and macrophages, focusing on the hypothesis of a possible direct lineage. This study focuses on a freshly isolated murine MSC population known as PαSmMSCs (CD45−TER119−Sca-1+PDGFRα+). Transplanting PαSmMSCs from transgenic GFP mice into irradiated recipients produced GFP+cells expressing the macrophage markers CD45, CD68, and CD115, indicating a macrophage-like phenotype. Further analysis showed that PαSmMSCs cultured in macrophage differentiation media acquired characteristics of M2 macrophages (CD45, CD68, and CD206). These results were confirmed in two different mouse strains as well as in human MSCs (hMSCs). Single-cell RNA sequencing revealed macrophage-like and fibrocyte-like populations among the PαSmMSCs. These findings demonstrate the phenotypic plasticity of freshly isolated MSCs to transition into macrophage-like and/or fibrocyte-like states, which has not been reported, particularly in long-term cultured MSCs. This study provides new insights into MSC plasticity and its potential roles in immune regulation and tissue repair.
Iterative SCRaMbLE for Engineering Synthetic Genome Modules and Chromosomes
Authors: Lu Xinyu , Ciurkot Klaudia , Gowers Glen-Oliver F. , Shaw William M , Ellis Tom
Published: December 2024

Synthetic biology offers the possibility of synthetic genomes with customised gene content and modular organisation. In eukaryotes, building whole custom genomes is still many years away, but work inSaccharomyces cerevisiaeyeast is closing-in on the first synthetic eukaryotic genome with genome-wide design changes. A key design change throughout the synthetic yeast genome is the introduction of LoxPsym site sequences. These enable inducible genomic rearrangementsin vivovia expression of Cre recombinase via SCRaMbLE (Synthetic Chromosome Recombination and Modification by LoxPsym-mediated Evolution). When paired with selection, SCRaMbLE can quickly generate strains with phenotype improvements by diversifying gene arrangement and content in LoxPsym-containing regions. Here, we demonstrate how iterative cycles of SCRaMbLE can be used to reorganise synthetic genome modules and synthetic chromosomes for improved functional performance under selection. To achieve this, we developed SCOUT (SCRaMbLEContinuousOutput andUniversalTracker), a reporter system that allows SCRaMbLEd cells to be sorted into a high diversity pool. When coupled with long-read sequencing, SCOUT enables high-throughput mapping of genotype abundance and correlation of gene content and arrangement with growth-related phenotypes. Iterative SCRaMbLE was applied here to yeast strains with a full synthetic chromosome, and to strains with synthetic genome modules encoding the gene set for histidine biosynthesis. Five synthetic designs forHISmodules were constructed and tested, and we investigated how SCRaMbLE reorganised the poorest performing design to give improved growth under selection. The results of iterative SCRaMbLE serve as a quick route to identify genome module designs with optimised function in a selected condition and offer a powerful tool to generate datasets that can inform the design of modular genomes in the future.
FAK activity exacerbates disturbed flow-mediated atherosclerosis via VEGFR2-Cbl-NF-κB signaling
Authors: Murphy James M. , Kieu Tran Duyen Thi , Jeong Kyuho , Nguyen Ly , Nguyen Mai Thi , Tambe Dhananjay , Jo Hanjoong , Ahn Eun-Young Erin , Lim Ssang-Taek Steve
Published: December 2024

Atherosclerosis develops at predictable sites in the vasculature where branch points and curvatures create non-laminar disturbed flow. This disturbed flow causes vascular inflammation by increased endothelial cell (EC) barrier permeability and the expression of inflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1). Vascular endothelial growth factor receptor 2 (VEGFR2) is important for flow-induced EC inflammation; however, there are still some gaps in the signaling pathway. Focal adhesion kinase (FAK) is a protein tyrosine kinase whose expression has been implicated in flow-mediated signaling in ECs. However, the link between FAK and VEGFR2 in flow-mediated inflammation signaling has remained unelucidated. Here we found that priming of VEGFR2 with VEGF was critical for flow-mediated activation of FAK and NF-kB. Mechanistically, FAK activation triggers tyrosine phosphorylation of Casitas B-lineage lymphoma (CBL; an E3 ubiquitin ligase) that interacts with VEGFR2 under flow conditions. Further,Apoe-/-mice fed a western diet (WD) exhibited increased FAK activity within the atheroprone disturbed flow region of the inner aortic arch compared to the outer arch. Disturbed flow-induced FAK activation is associated with elevated VEGFR2 on the surface of ECs of the inner aortic arch, but not in the outer arch. Taken together, these data suggest that suppression of augmented FAK activity under disturbed flow may prove beneficial in reducing pro-inflammatory signaling of the endothelial layer.
Epigenetic silencing and blockade of latency reversal by an HIV-1 encoded antisense transcript
Authors: Li Rui , Daneshvar Kaveh , Ji Xinjie , Pleet Michelle , Igbinosun Grace , Iqbal Mohd. Shameel , Kashanchi Fatah , Mullen Alan C. , Romerio Fabio
Published: December 2024

The mechanisms that regulate human immunodeficiency virus 1 (HIV-1) latency are not fully elucidated. We reported that an HIV-1 antisense transcript (AST) induces epigenetic modifications at the HIV-1 promoter causing a closed chromatin state that suppresses viral transcription. Here we show that ectopic expression of AST in CD4+ T-cells from people with HIV-1 under antiretroviral therapy blocks latency reversal in response to pharmacologic and T-cell receptor stimulation, enforcing transcriptional silencing. We define structural domains and sequence motifs of AST contributing to its latency-promoting functions. Finally, we report an unbiased proteomics screen of AST interactors that revealed an array of previously known and potential new HIV-1-suppressive factors. Our studies identify AST as a first-in-class biological molecule capable of enforcing HIV-1 latency and with actionable curative potential.
The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir
Authors: Huang Szu-Wei , Briganti Lorenzo , Annamalai Arun S. , Greenwood Juliet , Shkriabai Nikoloz , Haney Reed , Armstrong Michael L. , Wempe Michael F. , Singh Satya Prakash , Francis Ashwanth C. , Engelman Alan N. , Kvaratskhelia Mamuka
Published: December 2024

Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during HIV-1 replication. Previous studies have mainly focused on elucidating LEN’s mode of action during viral ingress. Additionally, the inhibitor has been shown to interfere with mature capsid assembly during viral egress. However, the mechanism for how LEN affects HIV-1 maturation is unknown. Here, we show that pharmacologically relevant LEN concentrations do not impair proteolytic processing of Gag in virions. Instead, we have elucidated the primary mechanism for highly potent inhibition of HIV-1 maturation by sub-stoichiometric LEN:CA ratios. The inhibitor exerts opposing effects on formation of CA pentamers versus hexamers, the key capsomere intermediates in mature capsid assembly. LEN impairs formation of pentamers, whereas it induces assembly of hexameric lattices by imposing an opened CA conformation and stabilizing a dimeric form of CA. Consequently, LEN treatment results in morphologically atypical virus particles containing malformed, hyper-stable CA assemblies, which fail to infect target cells. Moreover, we have uncovered an inverse correlation between inhibitor potency and CA levels in cell culture assays, which accounts for LEN’s ability to potently (with pM EC50values) inhibit HIV-1 maturation at clinically relevant drug concentrations.

Author Summary

Lenacapavir (LEN) is the first-in-class HIV-1 capsid targeting antiretroviral that exhibits multimodal modality to inhibit both early and late steps of viral replication. Our studies here have elucidated previously undescribed structural and mechanistic bases for a highly potent antiviral activity of LEN during viral egress. These findings will inform clinical applications of LEN as a potent HIV-1 maturation inhibitor and aid the development of second-generation inhibitors targeting assembly of the mature viral capsid.
A CRISPRi Library Screen in Group BStreptococcusIdentifies Surface Immunogenic Protein (Sip) as a Mediator of Multiple Host Interactions
Authors: Firestone K , Gopalakrishna KP , Rogers LM , Peters A , Gaddy JA , Nichols C , Hall MH , Varela HN , Carlin SM , Hillebrand GH , Giacobe EJ , Aronoff DM , Hooven TA
Published: December 2024

Group BStreptococcus(GBS;Streptococcus agalactiae) is an important pathobiont capable of colonizing various host environments, contributing to severe perinatal infections. Surface proteins play critical roles in GBS-host interactions, yet comprehensive studies of these proteins’ functions have been limited by genetic manipulation challenges. This study leveraged a CRISPR interference (CRISPRi) library to target genes encoding surface-trafficked proteins in GBS, identifying their roles in modulating macrophage cytokine responses. Bioinformatic analysis of 654 GBS genomes revealed 66 conserved surface protein genes. Using a GBS strain expressing chromosomally integrated dCas9, we generated and validated CRISPRi strains targeting these genes. THP-1 macrophage-like cells were exposed to ethanol-killed GBS variants, and pro-inflammatory cytokines TNF-α and IL-1β were measured. Notably, knockdown of thesipgene, encoding the Surface Immunogenic Protein (Sip), significantly increased IL-1β secretion, implicating Sip in caspase-1-dependent regulation. Further, Δsipmutants demonstrated impaired biofilm formation, reduced adherence to human fetal membranes, and diminished uterine persistence in a mouse colonization model. These findings suggest Sip modulates GBS- host interactions critical for pathogenesis, underscoring its potential as a therapeutic target or vaccine component.
Exosomes for facial repair, regeneration and rejuvenation: comparison between different commercial products
Authors: Salvaggio Antonio , Privitera Anna , Ferruggia Greta , Zimbone Massimo , Brundo Maria Violetta
Published: December 2024

Exosomes have been studied as a potential therapeutic option for improving skin texture. The mode of action of exosomes for skin texture likely involves several mechanisms, including stimulation of collagen production, promotion of skin cell proliferation; reduction of oxidative stress; regulation of inflammatory and antioxidant responses; extracellular matrix remodeling, which is important for maintaining skin structure and function. Aim of this study is to compare thein vitroeffects of some commercial products that use new technologies containing plant derived nanovesicles fromRosa damascenacallus,Centella asiaticacallus,Euphorbia supinastem and exosomes from bovine colostrum passively loaded with growth factors and cytokines purified from bovine colostrum, for facial repair, regeneration and rejuvenation. Of all the products tested, only product containing exosomes purified from colostrum gave very encouraging results in terms of effects on proliferation, cell viability and wound repair. The other products tested gave results comparable to the untreated samples.
Adoption challenges of sensing technologies in construction project management in sub-Saharan African countries
Authors: Ibrahim Kabir , Amoah Christopher , Simpeh Fredrick , William Justice
Published: December 2024

Purpose

The use of technology has increased in the industrial sector over the years. This has propelled the construction industry to follow suit by enhancing construction technology to experience the associated benefits. However, technology adoption in the construction environment has not been smoothly implemented. This article aimed to determine the obstacles to adopting sensing technology in managing construction projects in three major sub-Saharan African nations.

Design/methodology/approach

The study adopted a quantitative approach using structured questionnaires. The questionnaire link was sent to construction professionals in Nigeria, Ghana and South Africa, of which 120 were responded. Data received were analysed using the Statistical Package for Special Science (SPSS) to generate mean scores and the Kruskal–Wallis test and component analysis.

Findings

The results show that construction professionals face herculean tasks when adopting sensing technology in construction project management. Some prominent challenges are initial cost, lack of proper information technology (IT) infrastructure, power supply, lack of well-trained staff, maintenance cost, operating cost, cost of training, technology immaturity and resistance to change. The results also revealed that adoption challenges differ in these three countries, which may be attributable to the economic development level.

Practical implications

Despite the importance of sensing devices in construction industries, the study has revealed that Sub-Saharan African countries face enormous challenges in adopting them in project management and execution. This situation may hinder the industry’s ability to benefit from this technology in terms of efficiency, effectiveness and safety management, which may ultimately affect their cash flows.

Originality/value

The study provides a valuable understanding of the challenges encountered in implementing sensing technology in the construction sector in major countries within sub-Saharan Africa. These findings will enable the countries examined and other African countries to become cognizant of the challenges and implement strategies to overcome them, thereby enhancing performance in the construction industry.
Ventricular Tachycardia Possibly Originated From the His‐Purkinje System May Result From Aconitine Poisoning
Authors: Ni Honglin , Zhai Changlin , Pan Haihua
Published: December 2024

Accurate diagnosis of wide QRS complex tachycardia (WCT) with the earliest ventricular origin potentially located in the His‐Purkinje system, and exploration of its etiology are helpful for further diagnosis and treatment. This article finds through specific cases that one of the possible etiologies is aconitine poisoning.
Comparable outcomes among etiologies in early‐stage hepatocellular carcinoma: Analysis of a nationwide registry in Japan
Authors: Okushin Kazuya , Tateishi Ryosuke , Hirakawa Shinya , Tachimori Hisateru , Uchino Koji , Nakagomi Ryo , Yamada Tomoharu , Nakatsuka Takuma , Minami Tatsuya , Sato Masaya , Fujishiro Mitsuhiro , Hasegawa Kiyoshi , Eguchi Yuichiro , Kanto Tatsuya , Yoshiji Hitoshi , Izumi Namiki , Kudo Masatoshi , Koike Kazuhiko
Published: December 2024

Aim

Tumor stage and liver function determine the prognosis of patients with hepatocellular carcinoma (HCC). However, prognosis may differ depending on etiology. This study aimed to investigate etiological differences in the prognosis of patients with HCC.

Methods

We enrolled patients initially diagnosed with HCC and curatively treated with resection or ablation between 2018 and 2021 from a Japanese nationwide registry. The patients were grouped into hepatitis B (HBV), hepatitis C (HCV), and non‐B, non‐C. Viral status was also assessed. The end‐points were overall survival and decompensation‐free survival. We applied inverse probability of treatment weighting to draw adjusted Kaplan–Meier curves.

Results

Of the 4568 patients, 3546 underwent resection and 1022 underwent ablation. Hepatitis B virus DNA was undetectable in 45.2% of patients with HBV, and a sustained virologic response was achieved in 42.7% of patients with HCV at the initial diagnosis of HCC. In the resection cohort (13.9% HBV, 29.4% HCV, and 56.0% non‐B, non‐C), the adjusted overall survival showed no significant difference between non‐B, non‐C versus HBV (p = 0.57, log‐rank test) and non‐B, non‐C versus HCV (p = 0.68). Decompensation‐free survival was also similar among etiologies. In the ablation cohort (11.1% HBV, 44.2% HCV, and 43.9% non‐B, non‐C), there was also no significant difference in adjusted survival among etiologies.

Conclusion

Prognosis of patients with HCC was similar among different etiologies after adjusting for tumor stage and liver function. Nearly half of the patients with viral hepatitis achieved viral suppression or eradication at the initial diagnosis of HCC in Japan.
Autologous Cell‐Free Fat Extract: A Novel Approach for Infraorbital Rejuvenation—A Pilot Study
Authors: Cai Yizuo , Jia Zhuoxuan , Gu Jiancheng , Kang Bijun , Li Wei , Zhang Wenjie
Published: December 2024

Background and Objective

CEFFE (Cell‐free fat extract) treatment for periocular fine lines requires thorough clinical evaluation to determine its efficacy and safety in enhancing skin quality. The research enrolled 10 healthy female participants aged 31–58, focusing on skin texture, elasticity, and barrier function.

Methods and Results

CEFFE treatment demonstrated significant benefits, with notable improvements observed as early as 3 months posttreatment, which continued throughout the 12‐month follow‐up period. Objective assessments revealed reductions in SEr% and SEw%, indicative of reduced skin roughness and wrinkles, particularly pronounced after the third month of treatment. Enhanced skin elasticity, as indicated by improvements in R2%, R5%, and R7%, was observed, with the most significant enhancements noted at the 6‐month follow‐up. Furthermore, TEWL decreased consistently, highlighting CEFFE's potential in maintaining the skin's barrier function and moisture retention. High patient satisfaction levels, with 70% expressing satisfaction ranging from satisfied to very satisfied, underscored CEFFE's clinical significance.

Conclusions

CEFFE demonstrates potential as an effective and safe intervention for addressing periocular fine lines, providing a solution for fine lines while ensuring skin health (ChiCTR1900024329).
Evaluating the Efficacy of Combined Platelet‐Rich Plasma and Microneedling for Aesthetic Rejuvenation of the Periorbital Area: A Randomized, Blinded Cohort Study
Authors: Hassan Sally Al , Saade Dana S. , Kurban Mazen , Rahal Jihane Abou , Alameddine Ramzi M.
Published: December 2024

Introduction

Microneedling, a technique involving controlled dermal microwounding, and platelet‐rich plasma (PRP) injections are both employed for skin rejuvenation. While both treatments individually show promise, limited research has explored their combined efficacy. This study aimed to evaluate the effectiveness of combining PRP injections with microneedling for aesthetic concerns around the eyes under standardized conditions.

Methods

This single‐center, longitudinal cohort study was conducted from October 2017 to October 2020. Thirteen adult participants (mean age 35, 92.3% female) with aesthetic concerns in the periorbital area underwent combined PRP and microneedling treatment. Standardized photographs were taken preprocedure, at 1 week, and 3 months. Photographs were evaluated by three blinded dermatologists using validated photonumeric scales. Participants completed a self‐assessment questionnaire at the 1‐week follow‐up regarding skin homogeneity, texture, pigmentation, and wrinkles.

Results

Self‐reported outcomes indicated perceived improvements in skin homogeneity (72.7% reporting mild or significant improvement) and texture (81.8% reporting mild, moderate, or significant improvement). Improvements in pigmentation and wrinkles were less pronounced. Dermatologists' assessments revealed no significant differences in skin attributes before and after treatment.

Conclusion

Despite subjective reports of improvement, objective evaluations by independent dermatologists did not demonstrate significant changes. Variability in outcomes might be attributed to differences in study design, treatment protocols, and assessment methods. Further research with larger sample sizes and multiple treatment sessions is needed to better understand the benefits of combining PRP with microneedling for periorbital rejuvenation.
An R2R3‐type MYB transcription factor, GmMYB77, negatively regulates isoflavone accumulation in soybean [Glycine max (L.) Merr.]
Authors: Liu Yitian , Zhang Shengrui , Li Jing , Muhammad Azam , Feng Yue , Qi Jie , Sha Dan , Hao Yushui , Li Bin , Sun Junming
Published: December 2024

Soybean [Glycine max (L.) Merr.] is an exceptionally rich in isoflavones, and these compounds attach to oestrogen receptors in the human body, lessening the risk of breast cancer and effectively alleviating menopausal syndrome symptoms. Uncovering the molecular mechanisms that regulate soybean isoflavone accumulation is crucial for enhancing the production of these compounds. In this study, we combined bulk segregant analysis sequencing (BSA‐seq) and a genome‐wide association study (GWAS) to discover a novel R2R3‐MYB family gene, GmMYB77, that regulates isoflavone accumulation in soybean. Using the soybean hairy root transient expression system, we verified that GmMYB77 inhibits isoflavone accumulation. Furthermore, knocking out GmMYB77 significantly increased total isoflavone (TIF) content, particularly malonylglycitin, while its overexpression resulted in a notable decrease in contents of malonylglycitin and TIF. We found that GmMYB77 can directly binds the core sequence GGT and suppresses the expression of the key isoflavone biosynthesis genes Isoflavone synthase 1 (GmIFS1), Isoflavone synthase 2 (GmIFS2), Chalcone synthase 7 (GmCHS7) and Chalcone synthase 8 (GmCHS8) by using dual‐luciferase assays, electrophoretic mobility shift assays and yeast one‐hybrid experiments. Natural variations in the promoter region of GmMYB77 affect its expression, thereby regulating the malonylglycitin and TIF contents. Hap‐P2, an elite haplotype, plays a pivotal role in soybean breeding for substantially enhanced isoflavone content. These findings enhance our understanding of the genes influencing soybean isoflavone content and provide a valuable genetic resource for molecular breeding efforts in the future.
Construction and infection characteristics of a GFP‐labelled Botryosphaeria dothidea causing kiwifruit soft rot disease
Authors: Song Jinhuang , Shu Yiyang , Zheng Yanfei , Zhao Zhibo , Long Youhua , Fan Rong
Published: December 2024

Soft rot disease caused by Botryosphaeria dothidea is one of the most important fungal diseases affecting kiwifruit production. The symptoms of the disease generally appear during the fruit storage period, resulting in difficult disease management and serious economic losses. Therefore, the characterization of the infection mechanism needs to be explored to deepen our understanding of the pathogen and the disease. In this study, a highly pathogenic strain JY‐1, causing kiwifruit soft rot, was isolated and identified as B. dothidea. A polyethylene glycol‐mediated genetic transformation system for B. dothidea JY‐1 was established, enabling the successful acquisition of a green fluorescent protein (GFP)‐labelled strain with stable inheritance. The GFP‐labelled transformant Bd13 was generated and used in the research, and the infection process of kiwifruit tissues was studied through wound inoculation essays and fluorescence labelling microscopy. The results of the present study indicate that the transformant Bd13 not only damaged the kiwifruit fruits but also effectively infected and colonized the leaves and shoots of kiwifruit plants, causing shoot blight and leaf spot. These findings contribute to a deeper understanding of the pathogenic mechanisms underlying kiwifruit soft rot and lay a foundation for further investigations into the interaction between the soft rot pathogen B. dothidea and kiwifruit.
CRISPR/Cas9‐driven double modification of grapevine MLO6‐7 imparts powdery mildew resistance, while editing of NPR3 augments powdery and downy mildew tolerance
Authors: Moffa Loredana , Mannino Giuseppe , Bevilacqua Ivan , Gambino Giorgio , Perrone Irene , Pagliarani Chiara , Bertea Cinzia Margherita , Spada Alberto , Narduzzo Anna , Zizzamia Elisa , Velasco Riccardo , Chitarra Walter , Nerva Luca
Published: December 2024

The implementation of genome editing strategies in grapevine is the easiest way to improve sustainability and resilience while preserving the original genotype. Among others, the Mildew Locus‐O (MLO) genes have already been reported as good candidates to develop powdery mildew‐immune plants. A never‐explored grapevine target is NPR3, a negative regulator of the systemic acquired resistance. We report the exploitation of a cisgenic approach with the Cre‐lox recombinase technology to generate grapevine‐edited plants with the potential to be transgene‐free while preserving their original genetic background. The characterization of three edited lines for each target demonstrated immunity development against Erysiphe necator in MLO6‐7‐edited plants. Concomitantly, a significant improvement of resilience, associated with increased leaf thickness and specific biochemical responses, was observed in defective NPR3 lines against E. necator and Plasmopara viticola. Transcriptomic analysis revealed that both MLO6‐7 and NPR3 defective lines modulated their gene expression profiles, pointing to distinct though partially overlapping responses. Furthermore, targeted metabolite analysis highlighted an overaccumulation of stilbenes coupled with an improved oxidative scavenging potential in both editing targets, likely protecting the MLO6‐7 mutants from detrimental pleiotropic effects. Finally, the Cre‐loxP approach allowed the recovery of one MLO6‐7 edited plant with the complete removal of transgene. Taken together, our achievements provide a comprehensive understanding of the molecular and biochemical adjustments occurring in double MLO‐defective grape plants. In parallel, the potential of NPR3 mutants for multiple purposes has been demonstrated, raising new questions on its wide role in orchestrating biotic stress responses.
Ditopic Centrosymmetric Mercaptobenzothiazole Dilithium Salts: From the Molecular Complex to Luminescent 1D Coordination Polymers
Authors: Rogozhin A. F. , Ilichev V. A. , Silantyeva L. I. , Kozlova E. A. , Fukin G. K. , Bochkarev M. N.
Published: December 2024

The reaction of lithium amide LiN(Si(Me)3)2 and ditopic heterocyclic ligand benzo[1,2-d:4,5-d′]bis(thiazole)-2,6(3H,7H)-dithione (H2L) in dimethoxyethane (DME) affords the binuclear molecular complex Li2L(DME)4 (I). New compounds [Li2L(DMSO)4·(DMSO)2]n (II) and [Li2L(DMSO)4·(THF)2]n (III) are prepared by the recrystallization of compound I using a DMSO–diethyl ether or DMSO/THF mixture of solvents, respectively. According to the XRD data, these compounds are one-dimensional Coordination polymer (CPs) differed by the arrangement of the bis(thiazole) fragments relative to each other and the Li2O2 fragment in the polymer chain, which affects the luminescence properties. The molecular structures of compounds I–III are determined by XRD (CIF files CCDC nos. 2334192 (I), 2334193 (II), and 2334194 (III)).
CSF GPNMB in Parkinson's disease: A potential association with age and microglial activation
Authors: Zhu Xi-Chen , Mizutani Yasuaki , Ohdake Reiko , Tatebe Harutsugu , Maeda Toshiki , Shima Sayuri , Ueda Akihiro , Ito Mizuki , Ito Shinji , Tokuda Takahiko , Watanabe Hirohisa
Published: December 2024

Background

Recent evidence suggests a link between glycoprotein non-metastatic melanoma protein B (GPNMB) and Parkinson's disease (PD) pathogenesis. Although elevated plasma GPNMB levels associated with disease severity have been reported in PD, cerebrospinal fluid (CSF) alterations remain elusive.

Objective

To explore CSF GPNMB alterations and its clinical significance in PD.

Methods

This study enrolled 118 sporadic PD patients and 40 controls. We examined the potential associations between CSF GPNMB levels and the clinical characteristics or biomarkers of neurodegenerative pathogenesis.

Results

PD patients had higher CSF GPNMB levels than controls ( p = 0.0159). In the PD group, CSF GPNMB levels correlated with age (age at examination: rs = 0.2511, p = 0.0061; age at onset: rs = 0.2800, p = 0.0021) and the severity of motor and cognitive dysfunction (MDS-UPDRS III score: rs = 0.1998, p = 0.0347; Mini-Mental State Examination score: rs = −0.1922, p = 0.0370). After correcting for multiple comparisons, the correlation with age at onset remained significant. CSF GPNMB levels were also positively correlated with CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in both the PD ( rs = 0.3582, p < 0.0001) and control ( rs = 0.4743, p = 0.0023) groups. Furthermore, multiple regression analysis revealed CSF sTREM2 level as the strongest determinant of CSF GPNMB levels in the PD group (t-value = 3.49, p = 0.0007).

Conclusions

Elevated CSF GPNMB levels, linked with age and microglial activation, may be a valuable marker for understanding the interplay between aging, neuroinflammation, and PD pathology.
Clinical prognostic factors in progressive supranuclear palsy: Implications for clinical trials
Authors: Marchand Félix , Blaise Anne-Sophie , Defebvre Luc , Cailliau Emeline , Bombois Stéphanie , Devos David , Moreau Caroline
Published: December 2024

Background

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with diverse clinical phenotypes, prompting the development of new diagnostic criteria known as the MDS-PSP classification. However, little is known about the prognostic value of this classification in order to better stratify patients for the clinical trials.

Objective

To assess the impact of the different clinical phenotypes according to the MDS-PSP classification on prognosis using the clinical milestones of death, severe dysphagia, institutionalization, and need for walking aid.

Methods

A prospective cohort of 205 PSP patients from Lille University Hospital was analyzed retrospectively. Patients were classified into different MSD-PSP phenotypes according to their clinical presentation after 3 years of follow-up. The milestones of death, severe dysphagia, institutionalization, and need for walking aid were recorded, and a survival analysis was performed to describe the prognosis of each disease presentation.

Results

Median survival time was 6.4 (interquartile range (IQR): 4.8–8.6) years and mean diagnostic delay from symptom onset was 38.1 ± 22.5 months. PSP Richardson Syndrome (PSP-RS) had a poorer survival rate and a higher occurrence of severe dysphagia and need for walking aid compared to PSP variants such as PSP Parkinsonism (PSP-P), PSP postural instability without ocular motor dysfunction (PSP-PI), and other rare phenotypes.

Conclusions

PSP-RS has a less favorable prognosis compared to PSP variants stratified according to the MDS-PSP classification. This classification could assist in selecting patients for clinical trials and help design outcomes that account for the disease heterogeneity.
International collaboration to improve knowledge on myotonic dystrophy type 2
Authors: Peric Stojan , Ivanovic Vukan , Ashley Emma-Jayne , Esparis Belen , Campbell Craig , Wenninger Stephan , Monckton Darren , Marini-Bettolo Chiara , Walker Helen , Voháňka Stanislav , Cumming Kleed , Łusakowska Anna , Hodgkinson Victoria , Cosyns Marjan , Rodrigues Miriam , Yiu Eppie , Mazanec Radim , Stevenson Tanya , Kostera-Pruszczyk Anna , Korngut Lawrence , Jagut Marlène , Schoser Benedikt , Forbes Robin , Poll Annie , Roxburgh Richard
Published: December 2024

Background:

The TREAT-NMD Global Registry Network is a global collaboration of neuromuscular disease registries, including myotonic dystrophy type 2 (DM2), which aims to facilitate collaborative research and clinical trials.

Objectives:

This study aimed to assess DM2 patients included in the network, and to analyse their socio-demographic and clinical features.

Methods:

Data were collected through email surveys sent to 16 TREAT-NMD myotonic dystrophy core member registries. 10 registries enrolled DM2 patients.

Results:

The total number of DM2 cases was 1,720, with the Czech, German, and USA registries enrolling the most patients (445, 430, and 339 cases, respectively). The highest rates were seen in Czechia and Serbia (4.2 and 2.0 registered per 100,000 population, respectively). High DM2:DM1 ratios were seen in Central Europe. The median age at registry entry was 51 years. Symptom onset occurred before age 20 in 14% of cases. One fifth of patients used an assistive device to walk, and 4% were non-ambulatory. Insertion of a pacemaker or implantable cardioverter-defibrillator was reported in 4% of subjects, while 7% used non-invasive ventilation.

Conclusions:

This represents the largest DM2 cohort assembled to date, providing demographic and clinical data for future research and trial recruitment, illustrating TREAT-NMD's international reach and the importance of capturing DM2 data.
How to assess cognitive decline when test administration changes across study waves? Harmonizing cognitive scores across waves in the China Health and Retirement Longitudinal Study
Authors: Wu Yingyan , Zhang Yuan S , Kobayashi Lindsay C , Mayeda Elizabeth Rose , Gross Alden L
Published: December 2024

Background

Conducting longitudinal cognitive analyses is an essential part of understanding the underlying mechanism of Alzheimer's disease, especially for social and health behavior determinants. However, the cognitive test administration is highly likely to change across time and thus complicate the longitudinal analyses. The China Health and Retirement Longitudinal Study assessed memory through word recall tests across five study waves from 2011 to 2020. Since 2018, changes in the test stimuli and administration posed challenges for longitudinal cognitive analyses.

Objective

To address differences in administration and to preserve differences attributed to characteristics such as age and education and to derive equated scores for use in longitudinal analyses in CHARLS.

Methods

To ensure consistent underlying test ability across waves in the full sample (N = 19,364), we derived a calibration sample (N = 11,148) balancing age, gender, and education. Within this sample, we used weighted equipercentile equating to crosswalk percentile ranks between 2015 and 2018/2020 scores, then applied the algorithm to the full sample.

Results

Mean original delayed word recall was higher in 2018 (4.3 words) and 2020 (5.1 words) versus 2015 (3.2 words). Following equating, scores in 2018 and 2020 aligned better with previous waves (2015, 2018, 2020 immediate means: 4.1, 3.6, 4.0; delayed: 3.2, 2.4, 2.9 words).

Conclusions

Equipercentile equating enables the derivation of comparable scores, facilitating longitudinal analysis when cognitive test administration procedures change over time. We recommended the use of equated scores for longitudinal analyses using CHARLS cognitive data.
Comparative analysis of pharmacists’ knowledge and perception on the utilization of precision medicine to reduce antimicrobial resistance in Lebanon and Greece
Authors: El Bizri Luna , Chreif Ahmad , Hariri Rayane , Yaghi Joseph , El Khoury André
Published: December 2024

Pharmacogenomics and precision medicine are promising new tools in the fight against antimicrobial resistance by providing personalized treatment approaches based on an individual genetic makeup. Pharmacists, equipped with appropriate education and tools, can play a significant role in integrating pharmacogenomics and precision medicine into clinical practice and lead the rational use of pharmacogenomics in daily patient care. Improving patient outcomes in primary healthcare settings is the ultimate output. To date, there has been a lack of assessment and comparison of the knowledge and perceptions of pharmacists across different countries. A self-administered questionnaire was sent to 223 participants from Greece and Lebanon. Results showed that 96% and 68% of the pharmacists in both countries were familiar with the terminology of antimicrobial resistance and precision medicine. A deeper investigation showed gaps concerning the profound understanding of antimicrobial resistance from the one health perspective and the preventive measures. Knowledge of pharmacogenomics, its tests, and the value of precision medicine was low in both groups, with more pronounced deficiencies in the Lebanese group. Additionally, pharmacists didn’t perceive their current role in implementing pharmacogenomics and precision medicine in the combat against antimicrobial resistance, but they expressed openness to future involvement in this area. This research can serve as a foundational tool to establish or adjust policies to allocate resources and support both systems and people to enhance precision medicine implementation in low-to-middle-income countries. Furthermore, it highlights the importance of leveraging the experiences and knowledge of high-income countries to effectively address the challenge of antimicrobial resistance.