bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomic and proteomic changes in leaves of rubber seedlings infected by Phytophthora palmivora
Authors: Kruaweangmol Pongsakorn , Ekchaweng Kitiya , Morakul Sumallika , Phaonakrop Narumon , Roytrakul Sittiruk , Tunsagool Paiboon
Published: January 2025

Phytophthora palmivora, an oomycete pathogen, induces leaf fall disease in rubber trees (Hevea brasiliensis), causing significant economic losses. Effective disease management requires an understanding metabolic dynamics during infection. This study employed untargeted metabolomic and proteomic analyses to investigate the response of rubber seedling leaves to P. palmivora infection. Metabolomic profiling revealed 1702 and 979 metabolite peaks in positive and negative ionization modes, respectively, with 212 metabolites identified after duplicate removal. Principal component analysis demonstrated distinct metabolic profiles between infected and non-infected leaves. Volcano plots indicated significant changes in 90 metabolites (P < 0.05, fold-change ≥ 2), with 20 showing increased levels and 70 showing decreased levels in infected leaves. Pathway analysis highlighted nine metabolic pathways, with alanine, aspartate, and glutamate metabolism being the most impacted. Proteomic analysis identified 391 proteins, with 283 in infected leaves and 253 in control leaves. Among these, 145 were common to both conditions, suggesting their roles in maintaining homeostasis and responding to stress. Unique proteins in infected leaves were linked to oxidative phosphorylation, ATP synthesis and metabolic adjustments, reflecting the increased energy demands. Control samples showed proteins related to growth and photosynthesis. Integrating metabolomic and proteomic data revealed significant alterations in energy metabolism pathways in response to infection. These findings enhance our understanding of rubber seedlings’ defense strategies against P. palmivora, with implications for improving plant resistance and disease management strategies.
Intraspecific Variation and Recent Loss of Ancient, Conserved Effector Genes in the Sudden Oak Death Pathogen Phytophthora ramorum
Authors: Cauldron Nicholas C. , Press Caroline M. , Weisberg Alexandra J. , Horta Jung Marília , Corcobado Tamara , Webber Joan F. , Kageyama Koji , Hieno Ayaka , Masuya Hayato , Uematsu Seiji , Scanu Bruno , Brasier Clive M. , Jung Thomas , Chang Jeff H. , Grünwald Niklaus J.
Published: January 2025

Members of the Phytophthora genus are responsible for many important diseases in agricultural and natural ecosystems. Phytophthora ramorum causes devastating diseases of oak, and tanoak stands in US forests and larch in the UK. The four evolutionary lineages involved express different virulence phenotypes on plant hosts, and characterization of gene content is foundational to understanding the basis for these differences. Recent discovery of P. ramorum at its candidate center of origin in Asia provides a new opportunity for investigating the evolutionary history of the species. We assembled, high-quality genome sequences of six P. ramorum isolates representing three lineages from Asia and three causing epidemics in western US forests. The six genomes were assembled into 13 putative chromosomes. Analysis of structural variation revealed multiple chromosome fusion and fission events. Analysis of putative virulence genes revealed variations in effector gene composition among the sequenced lineages. We further characterized their evolutionary history and inferred a contraction of crinkler-encoding genes in the subclade of Phytophthora containing P. ramorum. There were losses of multiple families and a near complete loss of paralogs in the largest core crinkler family in the ancestor of P. ramorum and sister species P. lateralis. Secreted glycoside hydrolase enzymes showed a similar degree of variation in abundance among genomes of P. ramorum lineages as that observed among several Phytophthora species. We found plasticity among genomes from multiple lineages in a Phytophthora species and provide insights into the evolutionary history of a class of anciently conserved effector genes.
New approaches in childhood IgE-mediated food allergy treatment
Authors: Gurel Deniz Ilgun , Anagnostou Aikaterini , Fiocchi Alessandro , Sharon Chinthrajah , Sahiner Umit , Sindher Sayantani , Arasi Stefania
Published: January 2025

Purpose of review

This review aims to provide an overview of the current and future treatment options for children with food allergies (FAs), highlighting the latest research findings and the potential impact of these new approaches on improving patients’ and caregivers’ quality of life.

Recent findings

In the last decade, many promising approaches have emerged as an alternative to the standard avoidance of the culprit food with the risk of severe accidental reactions. Desensitization through oral immunotherapy has been introduced in clinical settings as a therapeutic approach, and more recently also omalizumab. In addition, alternative routes of administration for immunotherapy, other biologics, small molecules, probiotics or prebiotics, microbiota transplantation therapy, IGNX001, and PVX108 are being investigated.

The portfolio of available treatment options for food allergies is increasing but several relevant unmet needs remain. This review aims to provide a brief overview of the existing and future treatment options for IgE-mediated food allergies.
Occupational allergy and climate change
Authors: Raulf Monika , Annesi-Maesano Isabella
Published: January 2025

Purpose of review

Climate change influences working conditions in various ways, affecting employee health and safety across different sectors. Climatic factors like rising temperatures, increased UV radiation, and more frequent extreme weather events pose risks to in both indoor and outdoor workers. Allergic diseases of the respiratory tract and the skin may emerge due to climate change. This review summarizes current aspects of both direct and indirect consequences of climate change and associated exposures in diverse work environments, focusing on occupational allergies.

Recent findings

Outdoor workers, in particular, are increasing susceptible to ubiquitous pollen allergens. Additionally, they may experience climate-related increases in allergens typically associated with specific workplaces, such as Cryptostroma corticale. Changes in production processes, along with altered workplaces exposures, can lead to new sensitizations and trigger allergies, representing indirect consequences of climate change. Furthermore, lifestyle changes aimed to promoting climate protection and sustainability (e.g. the introduction of insects as a protein source or using enzymes), may also contribute to the emergence of new allergens.

The emergence of new occupational sensitization sources from novel or modified allergen exposures must be addressed within the framework of workplace safety and health, necessitating proactive measures to safeguard workers and mitigate risks.
HER2 regulates autophagy and promotes migration in gastric cancer cells through the cGAS-STING pathway
Authors: Liang Panping , Li Zedong , Chen Zhengwen , Chen Zehua , He Fengjun , Jin Tao , Cao Yuwei , Yang Kun
Published: January 2025

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase—stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06–3.54; P = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.
The effects of xylazine on locomotion and motor behaviour in a planarian model
Authors: Taylor Ryan , Denette Eric , Walter-Goodspeed Ellie , Byrne Tom
Published: January 2025

In recent years, the recreational use of xylazine has increased dramatically in the USA. Although xylazine has been used as an anesthetic in veterinary medicine for decades, little is known about its behavioral effects. We took advantage of the planarian’s innate negative phototaxis, the reliable movement from the light side to the dark side of a Petri dish, to explore the organism’s suitability as an animal model for investigating the preclinical pharmacology of xylazine. In two experiments, we tested the effects of several doses of xylazine on locomotion by recording the latency to transition into an opaque area. Xylazine disrupted locomotion in a dose-dependent fashion. Larger doses first produced a period of hyperkinesia without forward motion. This was followed by a period of sedation. Physical stimulation disrupted sedation and evoked the resumption of locomotion. Data on the behavioral effects of xylazine outside of anesthesia and sedation are limited; therefore, the current study adds to a relatively small literature on the behavioral effects of xylazine.
Adipose-derived Stem Cells and Wound Healing Are Progressively Impaired Long-term After Radiotherapy in Mice
Authors: Yoshizumi Kayo , Saito Natsumi , Wu Yunyan , Shirado Takako , Asahi Rintaro , Mori Masanori , Yamamoto Yoshihiro , Sowa Yoshihiro , Yoshimura Kotaro
Published: January 2025

Background:

The pathogenesis of deterministic radiation damage is not clearly understood, but it has been reported that fibroinflammatory pathways are up-regulated. We hypothesized that the number of adipose-derived stem/stromal cells (ASCs) decline after radiotherapies, preventing normalization of fibrosis and angiogenesis, resulting in chronic radiation damages that progress over time.

Methods:

Dorsal skin of 8-week-old male BALB/cfC3H mice was irradiated with 10 Gy weekly for 4 weeks. At 1, 3, 6, 9, and 12 months after radiotherapy (n = 5, 5, 5, 5, and 4), tissue hemoglobin oxygen saturation, and time until epithelialization were evaluated. Skin biopsies were measured for thickness and CD34+/isolectin− stem/stromal cell count. Nonirradiated (NRT) controls were evaluated at each time point as well (n = 5 each).

Results:

Compared with NRT controls, time until epithelialization was significantly longer at 1 month (28 ± 3, P < 0.01); not statistically different at 3 months (16 ± 2, P = 0.32); and lengthened over time at 6 months (20 ± 2, P = 0.21), 9 months (28 ± 2, P < 0.01), and 12 months (26 ± 3, P < 0.01), as did tissue oxygen saturation. The number of CD34+/isolectin– ASCs decreased over time, at 1 month (5.3 ± 1.3, P = 0.01), 3 months (6.0 ± 1.4, P = 0.03), 6 months (4.0 ± 0.8, P < 0.01), 9 months (1.7 ± 0.5, P < 0.01), and 12 months (0.3 ± 0.5, P < 0.01). The subcutaneous fatty layer was significantly thinner at 3 months (116 ± 33, P < 0.01), 6 months (147 ± 22, P = 0.02), 9 months (52 ± 12, P = 0.04), and 12 months (89 ± 19, P = 0.04), but not at 1 month (141 ± 18, P = 0.43).

Conclusions:

After 6 months postirradiation, the number of ASCs continued to decline over time, accompanied by irreversible progression of fibrosis, atrophy, and ischemia, which resulted in impaired wound healing.
Secondary Healing Over NovoSorb BTM in the Management of Complex Nasal Defects
Authors: McMahon Mary Ellen , Browne Robert , Ibrahim Safwat
Published: January 2025

Background:

The use of PolyNovo NovoSorb biodegradable temporizing matrix (BTM) has become popular for the management of complex wounds, often with the subsequent application of a split-thickness skin graft. To date, there are no published case series describing healing via secondary intention over BTM in the management of small, complex nasal wounds following excision of skin malignancy in the elective setting.

Methods:

This study consisted of a single-center, consecutive case series. Inclusion criteria consisted of defects with exposed cartilage or bone in wounds located on the nasal dorsum or nasal sidewall resulting from the elective excision of nasal skin malignancies. BTM without skin grafting was used as a single-stage reconstruction in all patients following oncological clearance. After delamination, the wound was left to heal by secondary intention. The Patient and Observer Scar Assessment Scale was used to measure the aesthetic outcome.

Results:

All 32 cases exhibited 100% integration of BTM and successful wound closure. Two cases required further excision following review of the final histology. The median (SD) overall Patient and Observer Scar Assessment Scale score was 2.7 (±0.81), and the median overall observer score was 3.2 (±0.73).

Conclusions:

When planning nasal reconstruction following oncological resection, one should consider the patient’s comorbidities; their ability to tolerate the anesthetic, surgery, donor skin deficit, and risks; and the technical ability of the operating surgeon. We suggest that the use of BTM without harvesting a skin graft represents a simple, low-risk option for reconstruction of nasal defects that produces acceptable functional and aesthetic outcomes.
Characterization changes and research waste in randomized controlled trials of global gastroesophageal reflux disease and hiatus hernia over the past 20 years
Authors: Lin Bin , Guo Xiao-Jing , Jiang Yi-Ming , Shang-Guan Zhi-Xin , Zhong Qing , Chen Qi-Yue , Xie Jian-Wei , Li Ping , Zheng Chao-Hui , Huang Chang-Ming , Lin Jian-Xian
Published: January 2025

Background:

The results of many large randomized clinical trials (RCTs) have transformed clinical practice in gastroesophageal reflux disease (GERD) and esophageal hiatal hernia (HH). However, research waste (i.e., unpublished data, inadequate reporting, or avoidable design limitations) remains a major challenge to evidence-based medicine. To explore the characteristics of GERD and HH RCTs over the past 20 years and whether there is research waste, and to explore potential targets for improvement.

Method:

A cross-sectional analysis was conducted to comprehensively review and evaluate RCTs related to GERD and esophageal HH, registered in the ClinicalTrials.gov database between 2003 and 2023. A sample of eligible RCTs was identified by excluding early-stage trials, pediatric studies, and duplicate studies. Publication status was tracked using PubMed and Scopus databases, reporting adequacy was assessed according to the CONSORT guidelines, and design flaws were checked with the help of Cochrane tools. Shortcomings of RCT studies in different regions and intervention types were identified by quantifying RCT conduct, recruitment, reporting adequacy, risk of bias, and guideline citations.

Results:

From 2003 to 2023, a total of 182 RCTs were included in the analysis, of which 69.8% (127 trials) were drug-related, and 71.4% of the principal investigators were located in North America and Asia (65 trials [35.7%] in both). Among them, the country with the most RCTs is the United States. RCTs in Asia were under-conducted in “procedure” and “other” types and fewer RCTs were conducted in Europe in “drug” type. RCTs in Oceania and South America were relatively under-conducted in the device and “other.” The study revealed that more than 86.7% of RCTs were characterized by at least one type of research waste. Research waste was associated with the size of the RCT, blinded design, and regional healthcare access and quality index.

Conclusions:

This study describes for the first time the characteristics of RCTs for GERD and esophageal HH over the past 20 years and the conduct of various types of RCTs at the continental level. It identifies the burden of research waste and shortcomings in the conduct of RCT programs on each continent, which may provide evidence for the development of rational RCTs and the reduction of waste in the future.
Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer
Authors: Rong Zeyin , Yang Jianhui , Liu Jiang , Meng Qingcai , Hua Jie , Tan Zhen , Zhang Bo , Liu Yuan , Du Qiong , Wang Wei , Yu Xianjun , Xu Jin , Liang Chen
Published: January 2025

Background:

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease.

Methods:

Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo. Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance.

Results:

PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1).

Conclusions:

The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.
Induction of M1 polarization in BV2 cells by propofol intervention promotes perioperative neurocognitive disorders through the NGF/CREB signaling pathway: an experimental research
Authors: Ye Ting , Fan Yiwei , Zeng Xiangye , Wang Xiaojing , Xiao Huaping
Published: January 2025

Nerve growth factor (NGF) is critical in regulating the homeostasis of microglial cells. It activates various signaling pathways that mediate the phosphorylation of cAMP response element-binding protein (CREB) at key regulatory sites. The decrease in phosphorylated CREB (p-CREB) expression is linked to neuroinflammatory responses. The exact molecular mechanism by which propofol regulates microglial polarization and induces neuroinflammation via the NGF/CREB signaling axis remains unclear. This study aims to investigate the specific mechanisms by which propofol induces perioperative neurocognitive disorders through microglial M1 polarization and neuroinflammation via the NGF/CREB signaling pathway. We demonstrated that propofol impairs neurocognitive function in mice, as evidenced by behavioral deficits. It reduces NGF expression in hippocampal microglia and BV2 cells, where protein-protein interactions between NGF and CREB suggest that NGF primarily regulates neurocognitive function by modulating p-CREB. Propofol intervention and inhibition of the NGF/CREB pathway promote M1 polarization in hippocampal microglia and BV2 cells, leading to reduced cell proliferation, increased apoptosis, elevated oxidative stress, and higher levels of the inflammatory marker TNF-α. Exogenous NGF does not alter the expression of NGF or total CREB but significantly upregulates p-CREB, indicating its regulatory role in signaling pathways associated with microglial activation. Moreover, exogenous NGF mitigates propofol-induced cognitive impairments and M1 polarization, reducing apoptosis and oxidative stress levels. Our findings suggest that propofol downregulates the expression of NGF and CREB, subsequently reducing p-CREB levels. This downregulation induces M1 polarization of microglia, promoting the progression of neuroinflammation and contributing to the development of perioperative neurocognitive disorders.
Early grafting using AlloDerm to lengthen the levator aponeurosis and correct upper eyelid retraction due to cosmetic blepharoplasty
Authors: Park Nam Seok , Lee Won , Kim Seong Hwan
Published: January 2025

Upper eyelid retraction (UER) often results from overcorrection of the levator palpebrae muscle during upper eyelid surgery. In such patients, the time between wound healing and reoperation may be prolonged and could result in symptoms, including dry eye. Therefore, the correction surgery, in which the levator aponeurosis which was shortened by cosmetic blepharoplasty is lengthened, should be performed as early as possible for better patient satisfaction and surgical outcomes. Between August 2020 and September 2022, we performed spacer grafting using AlloDerm dermal matrix after detaching the levator palpebrae muscle from the tarsus in 64 patients who experienced UER after bilateral eyelid surgery and cosmetic blepharoplasty. Among 64 patients, 50 (78%) had satisfactory results, 8 (12%) had blepharoptosis, and 6 (10%) had insufficient correction. Our method produced a normalized levator aponeurosis position, symmetric eyes, and reduced adverse effects, including surprised and dry eyes. In addition, the method is easy to follow and safe.
Improving Patient Transfer Quality: A Retrospective Study on a Transfer Center for a Canadian Upper Extremity Revascularization Program
Authors: Arsenault Virginie , Efanov Johnny I. , Lavoie Frédéric , Desrosiers Marie-Eve , Danino Michel A.
Published: January 2025

Background:

Centralization to trauma centers is the gold standard for digital revascularization, but avoidable transfers constitute a real challenge to the trauma network. Our transfer center is characterized by a 24/7 call center managed by specialized nurses responsible for data collection, pictures and imagery transmissions and arrangement of systematic recorded discussions between referring doctors and surgeons. This study investigated the impact of implementing a dedicated transfer center on avoidable patient transfers to a centralized quaternary care center for upper extremity injuries requiring revascularization.

Methods:

A retrospective study was performed from September 2017 to December 2021. We included all transfer requests from outside facilities to revascularize upper extremity injuries. Transfers were considered avoidable if no exploration or microsurgical vascular procedure was attempted. Univariate and multivariate analysis were employed to compare transfer outcomes before and after the addition of the transfer center in 2019.

Results:

795 transfer requests were analyzed, of which 326 occurred before the implementation of the transfer center and 469 occurred after. Following this addition, the incidence of transfer requests increased from 13.48 requests per month to 16.96 (p=0.016). It improved communications between referring doctors and surgeons and improved triage selection, resulting in an increase of transfer refusals (from 47% to 56%, p=0.009). Avoidable transfers significantly decreased by 7.32% (p=0.047) following the implementation of the standardized protocol and call center.

Conclusions:

Unnecessary interhospital transfers in the context of digital revascularization burden the trauma network. Introducing a dedicated transfer center reduces avoidable transfers by improving triage selection and communications.
Risk of Cancers According to the Use of Biological Agents in Patients With Radiographic Axial Spondyloarthritis
Authors: Kwon Oh Chan , Lee Hye Sun , Yang Juyeon , Park Min-Chan
Published: January 2025

Objective

As the duration of use of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with radiographic axial spondyloarthritis (r-axSpA) accumulates over time, long-term real-world safety data on cancer risk are needed. This study assessed the association between tumor necrosis factor inhibitors (TNFis) and interleukin 17 inhibitors (IL-17is) exposures and cancer risk in patients with r-axSpA.

Methods

From the Korean nationwide database, we assembled 41,889 patients without prior history of cancer who were diagnosed with r-axSpA from 2010 onwards. Patients were followed up through 2021. Multivariable time-varying Cox models were performed to estimate the adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs) of (1) overall cancers and (2) cancer subtypes according to TNFis exposure versus bDMARDs nonexposure, IL-17is exposure versus bDMARDs nonexposure, and IL-17is exposure versus TNFis exposure.

Results

The incident rates of overall cancers during bDMARDs nonexposure, TNFis exposure, and IL-17is exposure were 53.8, 37.6, and 67.3 per 10,000 person-years, respectively. TNFis exposure versus bDMARDs nonexposure was not associated with an increased risk of overall cancers (aHR = 0.9, 95% CI = 0.8–1.1). IL-17is exposure was not associated with an increased risk of overall cancers compared with bDMARDs nonexposure (aHR = 1.2, 95% CI = 0.5–3.0) or TNFis exposure (aHR = 1.3, 95% CI = 0.6–3.3). Similarly, no significant associations were observed between bDMARDs exposures and the risk of cancer subtypes.

Conclusions

In patients with r-axSpA, there was no evidence of increased cancer risk with TNFis and IL-17is exposures compared with bDMARDs nonexposure, suggesting that the use of bDMARDs is safe with respect to cancer risk in patients with r-axSpA.
Desulfosporosinus paludis sp. nov., an acidotolerant sulphate-reducing bacterium isolated from moderately acidic fen soil
Authors: Dyksma Stefan , Neumann-Schaal Meina , Müsken Mathias , Pester Michael
Published: January 2025

An obligately anaerobic, spore-forming sulphate-reducing bacterium, strain SB140T, was isolated from a long-term continuous enrichment culture that was inoculated with peat soil from an acidic fen. Cells were immotile, slightly curved rods that stained Gram-negative. The optimum temperature for growth was 28 °C. Strain SB140T grew at pH 4.0–7.5 with an optimum pH of 6.0–7.0 using various electron donors and electron acceptors. Yeast extract, sugars, alcohols and organic acids were used as electron donors for sulphate reduction. SB140T additionally used elemental sulphur and nitrate as electron acceptors but not sulphite, thiosulphate or iron(III) provided as ferrihydrite and fumarate. The 16S rRNA gene sequence placed strain SB140T in the genus Desulfosporosinus of the phylum Bacillota. The predominant cellular fatty acids were iso-C15 : 0 (52.6%) and 5,7 C15 : 2 (19.9%). The draft genome of SB140T (5.42 Mbp in size) shared 77.4% average nucleotide identity with the closest cultured relatives Desulfosporosinus acididurans M1T and Desulfosporosinus acidiphilus SJ4T. On the basis of phenotypic, phylogenetic and genomic characteristics, SB140T was identified as a novel species within the genus Desulfosporosinus, for which we propose the name Desulfosporosinus paludis sp. nov. The type strain is SB140T (=DSM 117342T=JCM 39521T).
Tracking Antimicrobial Resistant Organisms Timely (TAROT): A Workflow Validation Study for Successive Core-genome SNP-based Nosocomial Transmission Analysis
Authors: Aoki Kotaro , Komori Kohji , Yamaguchi Tetsuo , Harada Sohei , Tsukada Mayumi , Murakami Hinako , Tateda Kazuhiro
Published: January 2025

Background: Effective infection prevention and control (IPC) interventions in hospitals require timely information to determine the potential transmission of antimicrobial-resistant (AMR) organisms. Objectives: We validated a successive core-genome single nucleotide polymorphism (cgSNP)-based phylogenetic analysis workflow, ′Tracking Antimicrobial Resistant Organisms Timely′ (TAROT), with Oxford Nanopore Technologies (ONT) sequencer for methicillin-resistantStaphylococcus aureus(MRSA). Methods: We have developed a TAROT workflow for successive phylogenetic analysis using ONT data. We sequenced 34 MRSA strains isolated from Toho University Omori Medical Center using MinION (ONT) and MiSeq (Illumina). Each strain's ONT data were inputted into TAROT (TAROT-ONT), and successive cgSNP-based phylogenetic analyses were conducted. Illumina data were processed with a batched cgSNP-based phylogenetic analysis. Assembly-based analysis identified AMR genes, AMR mutations, and virulence genes. Results: MinION generated an average sequence depth of 262x for the ST8 reference genome within three hours. TAROT-ONT successively generated 11 phylogenetic trees for 14 ST8 strains, seven trees for 10 ST1 strains, and two trees for five ST5 strains. Highly suspected transmission pairs (pairwise cgSNP < 5) were detected in trees #6 through #11 for ST8, trees #3, #5, and #7 for ST1, and tree #2 for ST5. Differences in cgSNP value between TAROT-ONT and Illumina ranged from zero to two within pairs with fewer than 20 cgSNPs using Illumina. TAROT-ONT bioinformatic analysis for each strain required five to 42 minutes. The identification of AMR genes, mutations, and virulence genes showed high concordance between ONT and Illumina. Conclusion: TAROT-ONT facilitates effective IPC intervention for MRSA nosocomial transmissions by providing timely feedback through cgSNP-based phylogenetic analyses.
Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies
Authors: Lin Yunqing , Xiao Ziyun , Hu Fangxiao , Zheng Xiujuan , Zhang Chenyuan , Wang Yao , Liu Yanhong , Huang Dehao , Wang Zhiqian , Xia Chengxiang , Weng Qitong , Zhang Leqiang , Zhao Yaoqin , Qi Hanmeng , Shen Yiyuan , Chen Yi , Zhang Fan , Wu Jiaxin , Liu Pengcheng , Xu Jiacheng , Liu Lijuan , Zhu Yanping , Zhang Jingliao , Qian Wenbin , Liang Aibin , Zhu Xiaofan , Wang Tongjie , Zhang Mengyun , Wang Jinyong
Published: January 2025

Background: T cell malignancies are highly aggressive hematological tumors with limited effective treatment options. CAR-NK cell therapy targeting CD7 has emerged as a promising approach for treating T-cell malignancies. However, conventional CAR-NK cell therapy faces the challenges of cell fratricide due to CD7 expression on both malignant cells and normal NK cells. Additionally, engineering CARs into human tissue-derived NK cells demonstrates heterogeneity, low transduction efficiency, and high manufacturing costs. Methods: The human pluripotent stem cells (hPSCs) were genetically modified by knocking out the CD7 gene and introducing the CD7 CAR expression cassette to generate CD7 KO-CD7 CAR-hPSCs. These modified hPSCs were subsequently differentiated into CD7 KO-CD7 CAR-iNK cells using an efficient organoid induction method. The cytotoxicity of CD7 KO-CD7 CAR-iNK cells against CD7+ tumor cells was evaluated. Furthermore, we overexpressed the CXCR4 gene in CD7 KO-CD7 CAR-hPSCs and derived CXCR4-expressing CD7 KO-CD7 CAR-iNK (CRO-CD7 CAR-iNK) cells. The dynamics of CRO-CD7 CAR-iNK cells in vivo were tracked, and their therapeutic efficacy was assessed using human T-cell acute lymphoblastic leukemia (T-ALL) xenograft models. Results: The CD7 KO-CD7 CAR-iNK cells derived from CD7 KO-CD7 CAR-hPSCs effectively avoided fratricide, demonstrated normal expansion, and exhibited potent and specific anti-tumor activity against CD7+ T-cell tumor cell lines and primary T-ALL cells. CXCR4 overexpression in CRO-CD7 CAR-iNK cells improved their homing capacity and extended their persistence in vivo. The CRO-CD7 CAR iNK cells significantly suppressed tumor growth and prolonged the survival of T-ALL tumor-bearing mice. Conclusions: Our study provides a reliable strategy for the large-scale generation of fratricide-resistant CD7 CAR-iNK cells with robust anti-tumor effects from hPSCs, offering a promising cell product to treat T-cell malignancy.
Enhancing Immune Cell Activation through Cold Atmospheric Plasma: Disruption of PD-1/PD-L1/PD-L2 Immune Checkpoints via Molecular Dynamics
Authors: Rasulbek Mashalov , Toshpulatova Zulfizar , Chen Zhitong , Razzokov Jamoliddin
Published: January 2025

The PD-1/PD-L1/PD-L2 immune checkpoint plays a critical role in regulating immune responses, and its dysfunction is implicated in immune evasion by cancer cells. Cold atmospheric plasma (CAP) has emerged as a promising cancer therapeutic modality with the potential to modulate immune checkpoints. This study employs molecular dynamics (MD) simulations to investigate the impact of CAP-induced oxidation on the interactions between PD-1 and its ligands, PD-L1 and PD-L2. We simulated the PD-1/PD-L1 and PD-1/PD-L2 complexes under different oxidation levels. Key residues within the interaction site of the ligands are modified using Vienna PTM 2.0 online server. Umbrella sampling and other MD analyses revealed that increasing oxidation levels leads to weaken the binding affinity between PD-1 and both PD-L1 and PD-L2. These findings suggest that CAP may offer a novel strategy for enhancing anti-tumor immunity. This computational study provides valuable insights into the molecular mechanisms underlying CAP's effects on immune regulation and highlights its potential for cancer immunotherapy.
Identification of QTL for reproductive success under heat stress conditions through a tomato MAGIC population
Authors: Lin Ya-Ping , Hussain Ehtisham , Hsu Yun-Che , Lin Chen-Yu , Chen You-Syuan , Hsu Lung-Hsin , Hung Ching-Yuan , Huang Shu-Mei , Yen Jo-Yi , Eybishitz Assaf , Hanson Peter , Kang Seung Won , Hoshikawa Ken
Published: January 2025

Heat stress threatens tomato productivity by reducing pollen viability, fruit set, and consequently, overall yield. While heat-tolerant traits are predominantly found in wild tomatoes, the introgression of heat tolerance into elite cultivars remains challenging due to linkage drag. To address this issue, the World Vegetable Center developed a Multi-parent Advanced Generation Inter-Cross (MAGIC) population, derived from crosses between four heat-tolerant and disease-resistant cultivars. Phenotypic evaluations revealed that fruit number accounted for approximately 57% of reproductive output, making it a critical selection index for heat tolerance. A total of 16,350 SNPs were developed for the MAGIC population, and genome-wide association studies (GWAS) identified 50 QTLs linked to the evaluated traits. Notably, three QTLs on chromosomes 1, 3 and 11 emerged as hubs influencing multiple reproductive traits, underscoring their critical role in heat tolerance. SL4.0CH11_47205149 associated with fruit number was converted into a Kompetitive Allele-Specific PCR (KASP) marker and validated for its significant association with yield. The identification of key QTLs and the prioritization of fruit number as a primary determinant of reproductive success offer valuable insights for targeted breeding strategies.

Highlight

Number of fruits is crucial for selecting heat-tolerant tomatoes in open fields. A marker linked to high fruit production helps develop high-yielding tomatoes better suited to withstand climate change.
Soffritto: a deep-learning model for predicting high-resolution replication timing
Authors: Bolzan Dante , Ay Ferhat
Published: January 2025

Motivation: Replication Timing (RT) refers to the order by which DNA loci are replicated during S phase. RT is cell-type specific and implicated in cellular processes including transcription, differentiation, and disease. RT is typically quantified genome-wide using two-fraction assays (e.g., Repli-Seq) which sort cells into early and late S phase fractions followed by DNA sequencing yielding a ratio as the RT signal. While two-fraction RT data is widely available in multiple cell lines, it is limited in its ability to capture high-resolution RT features. To address this, high-resolution Repli-Seq, which quantifies RT across 16 fractions, was developed, but it is costly and technically challenging with very limited data generated to date. Results: Here we developed Soffritto, a deep learning model that predicts high-resolution RT data using two-fraction RT data, histone ChIP-seq data, GC content, and gene density as input. Soffritto is composed of a Long Short Term Memory (LSTM) module and a prediction module. The LSTM module learns long- and short-range interactions between genomic bins while the prediction module is composed of a fully connected layer that outputs a 16-fraction probability vector for each bin using the LSTM module embeddings as input. By performing both within cell line and cross cell line training and testing for five human and mouse cell lines, we show that Soffritto is able to capture experimental 16-fraction RT signals with high accuracy and the predicted signals allow detection of high-resolution RT patterns. Availability: Soffritto is available at https://github.com/ay-lab/Soffritto
Plasma proteomic analysis of intermuscular fat links muscle integrity with processing speed in older adults
Authors: Tanaka Toshiko , Rosano Caterina , Huang Xiaoning , Tian Qu , Landman Bennett A. , Moore Ann Z , Miljkovic Iva , Perry Andrew , Khan Sadiya , Kalhan Ravi , Carr John Jeffrey , Terry James G. , Yaffe Kristine , Walker Keenan , Candia Julián , Ferrucci Luigi
Published: January 2025

INTRODUCTION

More intermuscular fat (IMF) has been associated with lower cognitive performance and faster age-associated decline in cognitive function however, the mechanisms driving this relationship have not been fully elucidated. We utilized proteomic analyses to identify the molecular mediators of the association between IMF and cognition to gain further insight into the mechanisms underlying this association.

METHODS

In this cross-sectional study, the plasma proteomic profile of IMF was assessed in the Baltimore Longitudinal Study on Aging (BLSA; n=941, age=66.7±15.2) and validated in the Coronary Artery Risk Development in Young Adults Study (CARDIA; n=2451, age=50.2±3.6). The 7628 plasma proteins were assessed using an aptamer-based assay and tested for association with IMF from the thigh (BLSA) and abdomen (CARDIA). Processing speed assessed by Digit Symbol Substitution Test (DSST). Associations between the main exposures, outcome and mediators were evaluated using linear regression, and mediating effects were assessed by causal mediation analysis adjusting for age, sex, muscle area or muscle volume, self-reported race, and years of education.

RESULTS

Higher IMF was associated with lower DSST performance both in the BLSA and CARDIA studies. There were 722 plasma proteins associated with IMF in both the discovery and replication cohorts (FDR-adjusted p≤0.05). Of the 722 IMF-associated proteins, 26 (24 unique proteins) mediated the relationship between IMF and processing speed with mediation effects ranging from 2.8 to 20.9% (p≤0.05). Overrepresentation analysis of the IMF-associated proteins showed enrichment of proteins in synaptic function and organization, and growth factor binding (FDR-adjusted p≤0.05).

DISCUSSION

There is a robust proteomic signature explaining, at least in part, the link of IMF with DSST. This signature reflected neurological function and growth factor regulation, which are both implicated in lower processing speed. Reducing IMF through behavioral or pharmacological intervention may improve cognition through reduction in growth factor activity and improvements in synaptic activity.
Towards uniform recognition of child abuse in the Netherlands: implementing the Screening instrument for Child Abuse and Neglect (SCAN)
Authors: van den Heuvel E.A.L. , de Vries D.S. , de Jong- van Kempen B.M. , Bakx R. , Bos R.F. , van Empelen P. , Hoedeman F. , Kappen T.H. , Russel-Kampschoer I.M.B. , Puiman P. , Schouten M.C.M. , Teeuw A.H. , Zwaans C.J. , Nijhof S.L. , van de Putte E.M.
Published: January 2025

STUDY PURPOSE

This study investigates compliance with the Screening Instrument for Child Abuse and Neglect (SCAN screening) and the usability of SCAN screening and its follow-up tool (SCAN-FU) for SCAN-positive outcomes, in 9 Emergency Departments (EDs). It aims to address the decline in child maltreatment recognition observed over the past decade in Dutch EDs.

METHODS

SCAN screening and SCAN-FU were integrated into the ED-workflow and electronic health records (EHRs), supported by an implementation strategy, e-learning, policy manuals, and an awareness campaign. Compliance was evaluated by comparing pre- and post-implementation screening rates, with clinically relevant improvement defined as a ≥10% increase. Usability was assessed using the Measurement Instrument for Determinants of Innovations and semi-structured interviews. Subgroup analyses were conducted by hospital type, EHR, profession type, and years of working experience.

RESULTS

After implementation the average compliance rate increased from 57.5% to 70.5%, with 3 of 8 sites achieving a ≥10% improvement. Compliance rates varied by site, with academic EDs benefiting most. Compliance was influenced by EHR configurations. Usability analysis identified five facilitators (perception of responsibility, social support, self-efficacy, knowledge, and formal ratification by management) and one barrier (unsettled organisation). Users considered SCAN screening and SCAN-FU user-friendly, though perceived support differed between nurses and physicians due to role-specific factors.

RELEVANCE

SCAN screening can improve compliance in recognising child maltreatment, but tailored strategies are needed for further implementation. SCANs standardised approach enhances uniform data collection, enabling comparative analysis and interdisciplinary collaboration, advancing early detection of child maltreatment.
Development of a Deep-Learning Algorithm for Detecting Suspicious Breast Lesions on Chest CT
Authors: Zhang Hongyi , Johnson Jacob , Ngo Lawrence
Published: January 2025

A convolutional neural network (CNN) was trained and evaluated for detecting suspicious breast lesions on a large dataset of chest CT exams from a teleradiology practice covering over 2,000 hospital sites. Radiologists annotated any discrete nodules or masses appearing within breast tissue, and the model was tested on a held-out set. At a threshold achieving 0.99 specificity, the model demonstrated a sensitivity of 0.32 and a positive predictive value (PPV) of 0.50. In a scenario where sensitivity and specificity were balanced, the model achieved sensitivity and specificity of 0.79 each, resulting in a PPV of 0.10. The overall performance, as indicated by the area under the receiver operating characteristic curve (AUC), was 0.87. These results highlight the potential of an automated system to identify suspicious breast lesions on chest CT exams, thereby aiding in the opportunistic detection of malignancies.
Development and Validation of Natural Language Processing Algorithms in the ENACT National Electronic Health Record Research Network
Authors: Wang Yanshan , Hilsman Jordan , Li Chenyu , Morris Michele , Heider Paul M. , Fu Sunyang , Kwak Min Ji , Wen Andrew , Applegate Joseph R , Wang Liwei , Bernstam Elmer , Liu Hongfang , Chang Jack , Harris Daniel R. , Corbeau Alexandria , Henderson Darren , Osborne John D , Kennedy Richard E , Garduno-Rapp Nelly-Estefanie , Rousseau Justin F. , Yan Chao , Chen You , Patel Mayur B. , Murphy Tyler J. , Malin Bradley A. , Park Chan Mi , Fan Jungwei W. , Sohn Sunghwan , Pagali Sandeep , Peng Yifan , Pathak Aman , Wu Yonghui , Xia Zongqi , Loguercio Salvatore , Reis Steven E. , Visweswaran Shyam
Published: January 2025

Electronic health record (EHR) data are a rich and invaluable source of real-world clinical information, enabling detailed insights into patient populations, treatment outcomes, and healthcare practices. The availability of large volumes of EHR data are critical for advancing translational research and developing innovative technologies such as artificial intelligence. The Evolve to Next-Gen Accrual to Clinical Trials (ENACT) network, established in 2015 with funding from the National Center for Advancing Translational Sciences (NCATS), aims to accelerate translational research by democratizing access to EHR data for all Clinical and Translational Science Awards (CTSA) hub investigators. The present ENACT network provides access to structured EHR data, enabling cohort discovery and translational research across the network. However, a substantial amount of critical information is contained in clinical narratives, and natural language processing (NLP) is required for extracting this information to support research. To address this need, the ENACT NLP Working Group was formed to make NLP-derived clinical information accessible and queryable across the network. This article describes the implementation and deployment of NLP infrastructure across ENACT. First, we describe the formation and goals of the Working Group, the practices and logistics involved in implementation and deployment, and the specific NLP tools and technologies utilized. Then, we describe how we extended the ENACT ontology to standardize and query NLP-derived data, as well as how we conducted multisite evaluations of the NLP algorithms. Finally, we reflect on the experience and lessons learnt, which may be useful for other national data networks that are deploying NLP to unlock the potential of clinical text for research.
Using consideRATE to Evaluate Patient Experience in a Cancer Center: Psychometric and Healthcare Assessments
Authors: Nano Joseph P. , Stevens Gabrielle , Elwyn Glyn , Petrov Leeza , Gowrishankar Saahithya , Robitaille Shaday , Van Citters Aricca D. , Nelson Eugene C. , Wasp Garrett T. , Kirkland Kathryn B. , MacMartin Meredith A. , Saunders Catherine H.
Published: January 2025

Background

consideRATE is a patient- and care-partner-reported measure of care experience during serious illness. We usedconsideRATE with patients and care partners at the Dartmouth Cancer Center to assess patient experience, evaluate psychometric properties, and explore scoring approaches.

Methods

Patients and care partners aged 18+ and English proficient participated in a cross-sectional survey. Participants completedconsideRATE (8 items), CANHELP-Lite (21 items), and demographic questions. Reliability was assessed using Cronbach’s α, and validity was evaluated with Pearson’s correlations. Continuous and top-box scoring approaches were used. Psychometric properties were analyzed for patients, care partners, and subgroups with lower educational attainment or income.

Results

244 participants (114 patients,128 care-partners, 2 unspecified) completed the survey.consideRATE has internal reliability (α = 0.86); the correlation (r) betweenconsideRATE continuous scoring and CANHELP Lite scores for all participants was 0.5; p<0.001, for patients 0.5; p<0.001, for care-partners 0.5; p<0.001, for patients (n=71) with lower educational attainment 0.5, p<0.001, and for patients (n=50) with lower income 0.7, p<0.001. We also found correlations betweenconsideRATE top-box scoring and CANHELP Lite scores for all participants (rpb=0.4, p<0.001), with stronger associations among the patient (rpb=0.5, p<0.001) and lower income (rpb=0.4, p=0.005) subgroups. We found discriminant validity betweenconsideRATE and Single-item Health Literacy (SILs) measures for continuous scoring (r = -0.05 to 0.09, p>0.05) and top-box scoring (r = -0.02 to 0.09, p>0.05). We found no significant difference in overall experience between patients with breast and blood cancer.

Conclusion

We demonstrated in this sample of patients attending a cancer center thatconsideRATE has good internal reliability and is well correlated with CANHELP-Lite.