bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental Enrichment and Health Outcomes Among Low-Grade Glioma Brain Tumor Survivors
Authors: Figuracion Karl Cristie F. , Donald Christine Mac , Hunt David , McGranahan Tresa , Lewis Frances M. , Rockhill Jason , Goldberg Myron , Halasz Lia M. , Thompson Hilaire J.
Published: October 2024

BACKGROUND: Brain tumor survivors who received radiotherapy (RT) are at a disproportionately increased risk of accelerated aging and symptom burden. We aim to examine the association between environmental enrichment (EE) and health outcomes among low-grade glioma survivors who received brain RT. METHODS: The study used a cross-sectional cohort design, enrolling participants approximately 5 years from diagnosis. The construct of EE consisted of social network, physical activity, employment status, and financial stability. Berkman-Syme Social Network Index, International Physical Activity Questionnaire, Vocational Index Scale, and a Socioeconomic Questionnaire were used to measure the construct of EE. Health outcome measures included the Montreal Cognitive Assessment, Symbol Digit Modality Test, clinical brain magnetic resonance images (pre-RT, approximately 2-3 years after RT, and approximately 5 years after RT), Karnofsky Performance Status Scale, and the MD Anderson Symptom Inventory Brain Tumor Module. Ordinal logistic regression estimated the association between levels of EE and health outcomes. RESULTS: Thirty-nine participants completed the study and experienced varying levels of EE. The median age was 44 years old, ranging from 26 to 78 years old. Nineteen individuals were diagnosed with oligodendroglioma, and 18 were diagnosed with astrocytoma. Thirteen participants had low EE, 17 had moderate EE, and 9 had high EE. Although not statistically significant, we observed patterns of increasing health outcomes (Montreal Cognitive Assessment, Symbol Digit Modality Test, and Karnofsky Performance Status Scale) related to increasing levels of EE. CONCLUSION: This study is an initial exploration into the role of EE in health outcomes and survivorship programs for persons with glioma. Future research should assess EE before treatment or at the time of diagnosis and be longitudinal to accurately ascertain the association between EE and health outcomes. Comprehensive neuro-oncology survivorship programs structured to facilitate EE may reduce symptom burden, promote neuroplasticity, and improve cognitive and functional outcomes after brain radiation.
Comparative Analysis of Inflammatory Bowel Disease Management
Authors: Israel Ariel , Sharif Kassem , Zada Galit , Friedenberg Amir , Vinker Shlomo , Lahat Adi
Published: October 2024

Background:

Inflammatory bowel disease (IBD) encompasses chronic gastrointestinal disorders characterized by recurrent inflammation. Achieving mucosal healing and preventing disease progression are primary treatment goals.

Objectives:

This study aimed to compare disease characteristics, medication utilization, procedures performed, and hospitalizations between IBD patients treated in hospital and community settings using the Leumit Health Service database.

Design:

A retrospective cohort study was conducted using data from the Leumit Health Service, comprising 3020 patients diagnosed with IBD from January 2010 to December 2019.

Methods:

Patients were divided based on primary care setting: hospital-based or community-based. Data included demographic characteristics, disease type, medication usage, procedures, and outcomes. Statistical analyses assessed differences between groups.

Results:

Hospital-treated patients were significantly younger (49.4±18.4 vs. 40.4±18.7, P<0.001 ), had higher rates of Crohn’s disease (45.9% vs. 71.4%, P<0.001), exhibited higher inflammatory markers (calprotectin 768±2182 vs. 1305±2526, P<0.001), lower albumin (4.23±0.27 vs. 4.12±0.32, P<0.001), hemoglobin levels (13.4±1.6 vs. 12.9±1.6, P<0.001), and lower BMI (26.2±5.3 vs. 24.6±5.6, P<0.001) compared with community-treated patients. Hospital-treated patients had more endoscopic procedures, higher medication utilization rates, shorter treatment durations, and increased hospitalization occurrence (12.1% vs. 23.6%, P<0.001), length (0.67±3.34 vs. 1.45±5.88, P<0.001), and colectomies (4.73% vs. 15.8%, P<0.001).

Conclusions:

Disparities exist in IBD management between hospital and community settings, influenced by disease severity and treatment approaches. Hospital-based care is associated with more aggressive disease and intensive interventions, while community-based care may reflect milder disease and conservative management. Integrating specialized care models and personalized approaches across settings can optimize patient outcomes and health care delivery for IBD management. Further research is needed to understand these disparities’ underlying mechanisms and develop comprehensive care strategies.
End-of-life in Hepatocellular Carcinoma
Authors: Goble Spencer R. , Sultan Amir , Debes Jose D.
Published: October 2024

Objective:

Investigate the impacts of palliative care consults, race, and socioeconomic status on the prevalence of invasive procedures in patients with hepatocellular carcinoma (HCC).

Background:

Palliative care, race, and socioeconomic status can all influence end-of-life care preferences, but their roles in HCC have not been adequately explored.

Materials and Methods:

This is a cross-sectional study of patients with HCC from 2016 to 2019 using the National Inpatient Sample. Terminal and nonterminal hospitalizations were assessed with logistical regression evaluating associations between palliative care, race, income, and procedures along with do-not-resuscitate orders and cost. Procedures included mechanical ventilation, tracheostomy, and cardiopulmonary resuscitation (CPR) among others.

Results:

A total of 217,060 hospitalizations in patients with HCC were included, 18.1% of which included a palliative care encounter. The mean age was 65.0 years (SD = 11.3 y), 73.9% were males and 55.5% were white. Procedures were increased in terminal hospitalizations in black [CPR adjusted odds ratio (aOR) = 2.57, P < 0.001] and Hispanic patients (tracheostomy aOR = 3.64, P = 0.018) compared with white patients. Palliative care encounters were associated with reduced procedures during terminal hospitalizations (mechanical ventilation aOR = 0.47, P < 0.001, CPR aOR = 0.24, P < 0.001), but not in nonterminal hospitalizations. No association between income and end-of-life procedures was found. Palliative care was associated with decreased mean cost in terminal ($23,608 vs $31,756, P < 0.001) and nonterminal hospitalizations ($15,786 vs $19,914, P < 0.001).

Conclusions:

Palliative care is associated with less aggressive end-of-life care and decreased costs in patients with HCC. Black and Hispanic race were both associated with more aggressive end-of-life care.
Fibroblast growth factor 21: update on genetics and molecular biology
Authors: Barros Daniel R. , Hegele Robert A.
Published: October 2024

Purpose of review

Since its discovery, most research on fibroblast growth factor 21 (FGF21) has focused on its antihyperglycemia properties. However, attention has recently shifted towards elucidating the ability of FGF21 to lower circulating lipid levels and ameliorate liver inflammation and steatosis. We here discuss the physiology of FGF21 and its role in lipid metabolism, with a focus on genetics, which has up until now not been fully appreciated.

Recent findings

New developments have uncovered associations of common small-effect variants of the FGF21 gene, such as the single nucleotide polymorphisms rs2548957 and rs838133, with numerous physiological, biochemical and behavioural phenotypes linked to energy metabolism and liver function. In addition, rare loss-of-function variants of the cellular receptors for FGF21 have been recently associated with severe endocrine and metabolic phenotypes. These associations corroborate the findings from basic studies and preliminary clinical investigations into the therapeutic potential of FGF21 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia. Furthermore, recent breakthrough research has begun to dissect mechanisms of a potential FGF21 brain-adipose axis. Such inter-organ communication would be comparable to that seen with other potent metabolic hormones. A deeper understanding of FGF21 could prove to be further beneficial for drug development.

FGF21 is a potent regulator of lipid and energy homeostasis and its physiology is currently at the centre of investigative efforts to develop agents targeting hypertriglyceridemia and MASLD.
Health Promotion and Physical Wellness in Pediatric Physical Therapy
Authors: Wengrovius Carissa , Miles Cindy , Fragala-Pinkham Maria , O’Neil Margaret E.
Published: October 2024

Purpose:

A health promotion and physical wellness (HPPW) life course approach for pediatric physical therapy (PT) is recommended to improve children’s health outcomes across the lifespan.

Summary of Key Points:

A life course approach describes how a child’s individual responses to environmental factors influence health outcomes. Using HPPW strategies, pediatric physical therapists can identify health risks and promote positive outcomes. Outcome measures and intervention recommendations are outlined to assist therapists in integrating HPPW strategies to ensure a longitudinal plan of care and optimal health outcomes for children.

Conclusions and Recommendations for Clinical Practice:

A child’s health trajectory begins in the prenatal period and is influenced by individual and environmental factors. Pediatric PT uses child- and family-centered approaches and environmental assessments to design plans of care that address child and family HPPW goals. Incorporating HPPW strategies into pediatric PT facilitates positive health and physical wellness across a child’s lifespan.

See the video abstract for insights from the authors.

Video Abstract:

Supplemental digital content available at https://www.dropbox.com/scl/fi/3g468hj1rpxrrivbeses0/HPPW-Video-Abstract_1080.mp4?rlkey=4p1i8z1gynroz064zpx3alijz&st=8u0gqemz&dl=0.
Management of Frontal Bone Exposure Following Paramedian Forehead Flap for Nasal Reconstruction
Authors: Salisbury Frances K. , Koenig Zachary A. , Uygur Halil S.
Published: October 2024

The paramedian forehead flap is renowned for its versatility and can cover a wide range of nasal defect sizes. Most of the literature discussing outcomes of paramedian forehead flap reconstructions focuses on morbidity at the recipient site. Frontal bone exposure resulting from the use of the paramedian forehead flap is a rare but possible complication, especially when periosteum overlying the bone is damaged during surgery or during healing by secondary intention due to desiccation. In this case, a 53-year-old female underwent nasal reconstruction with a paramedian forehead flap for an extensive nasal defect after Mohs surgery and resection of residual basal cell carcinoma. She missed her postoperative follow-up visit, and her frontal bone was noted to be exposed before the division of the pedicle procedure. During the division of the pedicle, the frontal bone was burred, and a bilayer dermal regeneration matrix was applied. She underwent a split-thickness skin grafting from her thigh at 4 weeks. The graft take was 100%, and wound closure was achieved with an acceptable cosmetic outcome. The successful resolution of the complication through innovative surgical interventions highlights the importance of adaptive surgical strategies and thorough postoperative care, aiming to contribute to the existing body of knowledge and improve future clinical practices in reconstructive surgery.
HOUSING TEMPERATURE ALTERS BURN-INDUCED HYPERMETABOLISM IN MICE
Authors: Kingren Meagan Scott , Hall Jaycelyn Starr , Ross Taylor Joseph , Barre Mary Claire , Barlow Abigail , Morales Martin , Treas Lillie Danielle , Maxson Robert Todd , Teo Esther , Porter Craig
Published: October 2024

Mice used in biomedical research are typically housed at ambient temperatures (22°C–24°C) below thermoneutrality (26°C–31°C). This chronic cold stress triggers a hypermetabolic response that may limit the utility of mice in modeling hypermetabolism in response to burns. To evaluate the effect of housing temperature on burn-induced hypermetabolism, mice were randomly assigned to receive sham, small, or large scald burns. Mice recovered for 21 days in metabolic phenotyping cages at 24°C or 30°C. Regardless of sex or sham/burn treatment, mice housed at 24°C had greater total energy expenditure (P < 0.001), which was largely attributable to greater basal energy expenditure when compared to mice housed at 30°C (P < 0.001). Thermoneutral housing (30°C) altered adipose tissue mass in a sex-dependent manner. Compared to sham and small burn groups, large burns resulted in greater water vapor loss, regardless of housing temperature (P < 0.01). Compared to sham, large burns resulted in greater basal energy expenditure and total energy expenditure in mice housed at 24°C; however, this hypermetabolic response to large burns was blunted in female mice housed at 30°C, and absent in male mice housed at 30°C. Locomotion was significantly reduced in mice with large burns compared to sham and small burn groups, irrespective of sex or housing temperature (P < 0.05). Housing at 30°C revealed sexual dimorphism in terms of the impact of burns on body mass and composition, where males with large burns displayed marked cachexia, whereas females did not. Collectively, this study demonstrates a sex-dependent role for housing temperature in influencing energetics and body composition in a rodent model of burn trauma.
Prognostic Implications of Changes in Platelet Trajectories in Patients With Sepsis: A Retrospective Analysis Using the Medical Information Mart for Intensive Care-IV Database
Authors: Wang Yingxin , Wu Jiaqian , Shao Tenghao , Su Dan , Ma Xin , Yu Zhanbiao , Li Ning
Published: October 2024

Objective

Patients with sepsis often experience reductions or increases in platelet counts, but the implications of these temporal patterns on prognosis remain unclear. The aim of this study was to investigate the impact of changes in platelet trajectories on the clinical prognosis of sepsis.

Methods

This study was a retrospective analysis using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were identified from the database, and their platelet trajectories were categorized into four distinct models based on the changes in platelet counts over a period of 14 days post-diagnosis of sepsis. The effect of these trajectories on patient prognosis was subsequently evaluated.

Results

A total of 15,250 patients with sepsis were included to construct a model, and the following four distinct platelet count trajectories were identified: normal platelet levels (phenotype 1); persistently low platelet levels (phenotype 2); gradually increasing platelet levels exceeding the normal range (phenotype 3); and consistently significantly elevated platelet levels (phenotype 4). Statistically significant differences were found in the 28-day mortality, in-hospital mortality, and 90-day mortality among the four phenotypes. Multivariate regression analysis showed that compared to the group with normal platelet levels (phenotype 1), the group with persistently low platelet levels (phenotype 2) had higher in-hospital mortality (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16-1.54), 28-day mortality (OR = 1.69, 95% CI: 1.47-1.94), and 90-day mortality (OR = 1.50, 95% CI: 1.32-1.69). There was no difference in in-hospital mortality between phenotypes 3 and 4 compared to phenotype 1, although phenotype 4 showed an increase in 28-day mortality (p < 0.05), and phenotype 3 showed a decreasing trend in 90-day mortality (p < 0.05). The results of inverse probability weighting adjusted by regression were basically consistent with the above findings, except that there was no statistical difference in 28-day mortality between phenotype 4 and phenotype 1. In the subgroups based on age, weight, and antiplatelet drugs or therapies, there was an interaction between platelet levels and these factors.

Conclusion

In patients with sepsis, a decrease in platelet count is associated with increased mortality, while a moderate increase in platelet count can reduce 90-day mortality. However, for patients with persistently elevated platelet counts, caution is advised when using antiplatelet drugs or therapies, as it may increase mortality.
CIRCTMCO3 ALLEVIATES SEPSIS-INDUCED ACUTE KIDNEY INJURY VIA REGULATING MIR-218-5P/ZEB2 AXIS
Authors: Gong Yingfeng , Wei Na , Shi Peipei , Zhu Gang
Published: October 2024

Background: Growing evidence has found the critical role of circular RNAs (circRNAs) in sepsis-induced acute kidney injury (S-AKI). CircTMCO3 has been found to be involved in tumor microenvironment changes of ovarian cancer. This study aimed to explore whether circTMCO3 functions in S-AKI, and if so, to elucidate the molecular mechanism. Methods: CircTMCO3 expression was analyzed in lipopolysaccharide (LPS)-induced HK-2 cells and in the kidney tissues of mice treated with cecal ligation and puncture (CLP), respectively. Furthermore, the effects of circTMCO3 on S-AKI and the related mechanisms were evaluated in both models through gain- and/or loss-of-function strategies. Results: CircTMCO3 expression was suppressed in both S-AKI models. Upregulation of circTMCO3 mitigated LPS-induced apoptosis, oxidative stress, and inflammation in HK-2 cells. In contrast, circTMCO3 downregulation exacerbated LPS-induced injuries in HK-2 cells. Intravenous injection of circTMCO3 lentivirus to increase circTMCO3 expression improved renal function and attenuated kidney injury in S-AKI mice, as evidenced by the decrease in serum creatinine and blood urea nitrogen concentrations, amelioration of tubular pathological injury, reduction of renal cell apoptosis, and mitigation of oxidative stress and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, circTMCO3 directly targeted miR-218-5p, and the mimic of which abolished the protective effect of circTMCO3 in cell models. ZEB2 was identified to be a target of miR-218-5p; its downregulation not only reversed the impacts of miR-218-5p inhibitor on S-AKI, but also mitigated the effects mediated by circTMCO3 upregulation in vitro. Conclusions: CircTMCO3 protects against S-AKI by regulating miR-218-5p/ZEB2 axis, thereby mediating antiapoptotic, antioxidant, and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI.
Fundamental constraints to the logic of living systems
Authors: Solé Ricard , Kempes Christopher P. , Corominas-Murtra Bernat , De Domenico Manlio , Kolchinsky Artemy , Lachmann Michael , Libby Eric , Saavedra Serguei , Smith Eric , Wolpert David
Published: October 2024

It has been argued that the historical nature of evolution makes it a highly path-dependent process. Under this view, the outcome of evolutionary dynamics could have resulted in organisms with different forms and functions. At the same time, there is ample evidence that convergence and constraints strongly limit the domain of the potential design principles that evolution can achieve. Are these limitations relevant in shaping the fabric of the possible? Here, we argue that fundamental constraints are associated with the logic of living matter. We illustrate this idea by considering the thermodynamic properties of living systems, the linear nature of molecular information, the cellular nature of the building blocks of life, multicellularity and development, the threshold nature of computations in cognitive systems and the discrete nature of the architecture of ecosystems. In all these examples, we present available evidence and suggest potential avenues towards a well-defined theoretical formulation.
Identification of Mammaliicoccus fleurettii as the source of a methicillin-resistance gene in a First Nation reserve lake in Manitoba, Canada
Authors: Bashar Sabrin , Patidar Rakesh , Wai Alvan , White Dawn , Golding George R. , Farenhorst Annemieke , Kumar Ayush
Published: October 2024

Our study aimed to identify the bacterial source of a previously detected mobile antibiotic-resistance gene, mecA, found in a lake that serves as a source to a water treatment plant operated by a First Nation reserve. Three methicillin-resistant presumptive Staphylococcus spp. isolated from the sample using selective media were verified as mecA positive by PCR (polymerase chain reaction). MALDI-TOF (matrix-assisted laser desorption ionization–time-of-flight mass spectrometry) and whole genome sequencing of each isolate confirmed that all three were Mammaliicoccus fleurettii. Antibiotic-resistance gene analysis of the assembled genomes predicted mecA with 99.7% sequence identity, and phylogenetic analysis grouped our three mecA genes with the mecA allele from a methicillin-resistant strain of Staphylococcus aureus. Identifying microbial species known to harbour mobile antibiotic-resistance elements can provide greater depth of information about drinking water, an especially essential need in First Nation reserves where water quality too frequently is poor.
Assessment of absorbed dose in the hematopoietic stem cell layer of the bone marrow, assuming non-uniform distribution around the vascular endothelium of the bone marrow
Authors: Kobayashi Noriko
Published: October 2024

Recent studies have shown that hematopoietic stem cells (HSCs) are concentrated around the endothelium of the sinusoidal capillaries. However, the current International Commission on Radiological Protection (ICRP) dosimetry model does not take into account the heterogeneity of the bone marrow tissue and stem cell distribution. In this study, the absorbed doses to the stem cell layer in the perivascular HSC layer in the bone marrow from radionuclides inhaled into the body were estimated for the major beta- and alpha-nuclides and noble gases and compared with the absorbed dose based on the ICRP 60 and ICRP 103 recommendations. The absorbed doses to the bone marrow obtained from the model calculations were not significantly different from ICRP60 and ICRP103 for beta-nuclides but were much lower than previously estimated for alpha-nuclides, and the contribution of red bone marrow and blood sources was greater than that of trabecular bone for alpha-nuclides. Noble gases in the red bone marrow may also affect the bone marrow stem cell layer. The bone marrow dose assessment for alpha nuclides and noble gases should be re-examined using a precise model based on CT images from the perspective of occupational and public radiation protection.
Fungal spore seasons advanced across the US over two decades of climate change
Authors: Wu Ruoyu , Song Yiluan , Head Jennifer R. , Katz Daniel S. W. , Peay Kabir G. , Shedden Kerby , Zhu Kai
Published: October 2024

Phenological shifts due to climate change have been extensively studied in plants and animals. Yet, the responses of fungal spores—crucial organisms that play important roles in ecosystems and act as airborne allergens—remain understudied. This knowledge gap in global change biology hinders our understanding of its ecological and public health implications. To bridge this gap, we acquired a long-term (2003 ∼ 2022), large-scale (the continental US) dataset of airborne fungal spores collected by the US National Allergy Bureau. We first pre-processed the spore data by gap-filling and smoothing. Afterward, we extracted ten metrics describing the phenology (e.g., start and end of season) and intensity (e.g., peak concentration and integral) of fungal spore seasons. These metrics were derived using two complementary but not mutually exclusive approaches—ecological and public health approaches, defined as percentiles of total spore concentration and allergenic thresholds of spore concentration, respectively. Using linear mixed effects models, we quantified annual temporal shifts in these metrics across the continental US. We revealed a significant advancement in the onset of the spore seasons defined in both ecological (11 days, 95% confidence interval: 0.4 ∼ 23 days) and public health (22 days, 6 ∼ 38 days) approaches over two decades. Nevertheless, the total spore concentration in an annual cycle and in a spore allergy season tended to decrease over time. The earlier start of the spore season was significantly correlated with climatic variables, such as warmer temperatures and altered precipitations. Overall, our findings suggest possible climate-driven advanced fungal spore seasons, highlighting the importance of climate change mitigation and adaptation in public health decision-making.
Chromosomal instability promotes cell migration and invasion via EFEMP1 secretion into extracellular vesicles
Authors: Zheng Siqi , Tian Ruifang , Liu Yuanyuan , Wardenaar Rene , Shirzai Marjan , Kempe Laura , Dijkstra Emma , Warszawik Eliza , Suarez Peredo Rodriguez Maria , Sjollema Klaas , Bakker Petra L. , van Rijn Patrick , Borghesan Michaela , Paridaen Judith , Santaguida Stefano , Foijer Floris
Published: October 2024

Triple-negative breast cancer (TNBC) is characterised by high rates of chromosomal instability (CIN) and a tumour microenvironment (TME) modulated by extracellular vesicles (EVs). To assess how CIN might affect the TME in TNBC, we studied the EV landscape of TNBC cell lines with induced CIN. We find that CIN leads to increased secretion of EVs and that these EVs promote cell migration of recipient cells. EVs are enriched for extracellular matrix (ECM) proteins, including EFEMP1. Indeed, modulation of EFEMP1 levels in EVs significantly alters migration behaviour of EV-treated cells. We show that EFEMP1 expression is regulated by STAT1, and that EVs from STAT1-deficient cells no longer promote migration, which can be rescued by overexpression of EFEMP1 in STAT1-null cells. Xenografting TNBC cells with EFEMP1 enriched cells promotes migration in zebrafish embryos, suggesting that EFEMP1 expression is a factor that promotes metastasis. Together our results uncover a novel role for CIN in shaping the TME of TNBC and identify EFEMP1 as a potential therapeutic target to prevent cell migration within the TME.
WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer
Authors: Citron Francesca , Ho I-Lin , Balestrieri Chiara , Liu Zhaoliang , Yen Er-Yen , Cecchetto Luca , Perelli Luigi , Zhang Li , Montanez Luis Castillo , Blazanin Nicholas , Dyke Charles A. , Shah Rutvi , Attanasio Sergio , Srinivasan Sanjana , Chen Ko-Chien , Chen Ziheng , Scognamiglio Iolanda , Pham Nhung , Khan Hania , Jiang Shan , Pan Jing , Vanderkruk Ben , Leung Cecilia S. , Mattohti Mahinur , Rai Kunal , Chu Yanshuo , Wang Linghua , Gao Sisi , Deem Angela K. , Carugo Alessandro , Wang Huamin , Yao Wantong , Tonon Giovanni , Xiong Yun , Lorenzi Philip L. , Bonini Chiara , Zal M. Anna , Hoffman Brad G. , Heffernan Tim , Giuliani Virginia , Jeter Collene R. , Lissanu Yonathan , Genovese Giannicola , Di Pilato Mauro , Viale Andrea , Draetta Giulio F.
Published: October 2024

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.
Maintenance of parasite species diversity: Spatiotemporal niche partitioning and aggregation facilitate species coexistence
Authors: Ramesh Ashwini , McDermott-Sipe Olivia , Bashey-Visser Farrah
Published: October 2024

The maintenance of parasite diversity has historically taken a host-centric approach. Yet, many parasites are host generalists, and most parasites spend at least some time outside of their hosts. So, what mechanisms besides host-associated niche partitioning allow parasites to coexist? Using a year-long field survey and lab mesocosms, we examined whether environmental niche partitioning or aggregation could enable coexistence among soil-dwelling entomopathogenic nematodes. Field patterns along an elevational gradient reveal that species abundances differentiate with soil structure and moisture levels. Yet, most species strongly overlap within-sites throughout the year. Thus, niche partitioning alone is not sufficient to explain the coexistence of these species and other mechanisms are necessary to explain their coexistence. Aggregation at the within-site scale provides evidence for such a mechanism. Each species showed significant intraspecific clumping and largely random associations with other species. A mesocosm test of the consequences of intraspecific aggregation found that parasites at low or high densities limit their own population growth. Aggregation can promote negative feedback facilitating species coexistence. Our findings offer field-based evidence that spatiotemporal niche partitioning and aggregation both play a critical role in maintaining parasite species diversity, illustrating the importance of extending out view of parasites beyond their hosts.
Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin
Authors: Lemmex Andrew C.D. , Allred Jeremy , Ostergard Jason , Trask Jake , Bui Hannah N. , Anderson Michael J. M. , Kopp Benjamin , Streeter Oakley , Smiley Adam T. , Babilonia-Díaz Natalia S. , Blazar Bruce R. , Higgins LeAnn , Gordon Peter M. , Muretta Joseph M. , Gordon Wendy R.
Published: October 2024

Notch plays critical roles in developmental processes and disease pathogenesis, which has led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling, derived from a synthetic phage-display library targeting the notch Negative Regulatory Region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay and in Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19uM affinity for Notch. We addressed the low affinity by fusion to a membrane-associating domain derived from the β-Pore forming toxin Aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with similar efficacy to other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody, and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.
An attractor state zone precedes neural crest fate in melanoma initiation
Authors: McConnell Alicia M. , Chassé Maggie H. , Noonan Haley R. , Mito Jeffrey K. , Barbano Julia , Weiskopf Erika , Gosselink Irene F. , Prasad Meera , Yang Song , Abarzua Phammela , Lian Christine G. , Murphy George F. , Trapnell Cole , Zon Leonard I.
Published: October 2024

The field cancerization theory suggests that a group of cells containing oncogenic mutations are predisposed to transformation1, 2. We previously identified single cells inBRAFV600E;p53-/-zebrafish that reactivate an embryonic neural crest state before initiating melanoma3–5. Here we show that single cells reactivate the neural crest fate from within large fields of adjacent abnormal melanocytes, which we term the “cancer precursor zone.” These cancer precursor zone melanocytes have an aberrant morphology, dysplastic nuclei, and altered gene expression. Using single cell RNA-seq and ATAC-seq, we defined a distinct transcriptional cell attractor state for cancer precursor zones and validated the stage-specific gene expression initiation signatures in human melanoma. We identify the cancer precursor zone driver, ID1, which binds to TCF12 and inhibits downstream targets important for the maintenance of melanocyte morphology and cell cycle control. Examination of patient samples revealed precursor melanocytes expressing ID1, often surrounding invasive melanoma, indicating a role for ID1 in early melanomagenesis. This work reveals a surprising field effect of melanoma initiationin vivoin which tumors arise from within a zone of morphologically distinct, but clinically covert, precursors with altered transcriptional fate. Our studies identify novel targets that could improve early diagnosis and prevention of melanoma.
An adaptive autoregressive diffusion approach to design active humanized antibody and nanobody
Authors: Ma Jian , Wu Fandi , Xu Tingyang , Xu Shaoyong , Liu Wei , Yan Divin , Bai Qifeng , Yao Jianhua
Published: October 2024

Humanization is a critical process for designing efficiently specific antibodies and nanobodies prior to clinical trials. Developing widely recognized deep learning techniques or frameworks for humanizing conventional antibodies and nanobodies presents a valuable yet challenging task. Inspired by the effectiveness of diffusion models across various applications, we introduce HuDiff, an adaptive diffusion approach for humanizing antibodies and nanobodies from scratch, referred to as HuDiff-Ab and HuDiff-Nb, respectively. This approach begins the humanization process exclusively with complementarity-determining region (CDR) sequences, eliminating the need for humanized templates. On public benchmark datasets, the results of HuDiff-Ab’s humanized antibodies are more similar to experimentally humanized antibodies than to those of the Sapiens humanization model. Besides, humanized nanobodies produced by HuDiff-Nb exhibit a higher humanness score and greater nativeness than those generated by the Lammanade pipeline for humanization nanobody. We apply HuDiff to humanize a mouse antibody and an alpaca nanobody, both targeting the SARS-CoV-2 RBD, and validate the binding affinity of humanized sequences through Bio-Layer Interferometry (BLI) experiments. The results show the binding affinity of the best humanized antibody is nearly equal to that of the parental mouse antibody (0.15 nM vs. 0.12 nM). Remarkably, the top-performing humanized nanobody exhibits a significantly enhanced binding affinity compared to the parental alpaca nanobody (2.52 nM vs. 5.47 nM), representing a 54% increase. These findings indicate that our approach HuDiff is highly effective in enhancing the humanness of antibodies and nanobodies while maintaining or potentially improving the binding affinity of the designed humanized sequences. The code and checkpoints of HuDiff are available athttps://github.com/TencentAI4S/HuDiff.
Inhibition of UBE2N in regulatory T-cells boosts immunity against cancer
Authors: Miao Wanying , Jain Vaibhav , Han Madison , Jin Yingai J. , Beasley Georgia M. , Starczysnowski Daniel T. , Gregory Simon G. , Zhang Jennifer Y.
Published: October 2024

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2nTreg-KO) of adult mice results in a robust expansion and activation of cytotoxic CD8+T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.
Impact of land-use intensity, productivity, and aboveground richness on seed rain in temperate grasslands
Authors: Klinger Y.P. , Kunze S. , Hölzel N. , Freitag M. , Klaus V.H. , Kleinebecker T. , Prati D. , Neuenkamp L
Published: October 2024

Seed rain, the amount of seeds reaching an area via primary or secondary dispersal, affects the regeneration of plant communities and shapes the trajectory of future community composition. In agricultural grasslands, the composition and density in seed rain are mainly driven by land use, but drivers of seed rain quality and quantity along land-use gradients are poorly understood. We studied the effects of land-use intensity (LUI), its components (i.e. fertilization, mowing, and grazing), productivity, and aboveground vegetation composition and richness on seed rain.

We collected the seed rain over a five-month period in 142 grasslands and identified emerging seedlings. Grass seedlings dominated seed rain most likely due to their high abundance in vegetation and intense and early seed set. Only ten species accounted for approximately 80 % of seedlings, with grasses such asLolium perenneandAlopecurus pratensisbeing most abundant. Forbs such asCerastium holosteoidesandVeronica arvensiswere abundant in seed rain despite lower cover, probably due to early and prolonged flowering and high seed production.

Seed rain of grasses and forbs reacted differently to LUI and vegetation richness, LUI effects on grass seed rain mainly determined total seed density. Seed rain richness first increased with LUI, but decreased at higher LUI levels. Consequently, seed rain richness consistently increased with vegetation richness. This is reflected by a decrease in the abundance of stress strategists and an increase in ruderals in seed rain with increasing LUI and decreasing vegetation richness.

Among LUI components, fertilization intensity most strongly affected seed rain density and composition, with negative effects at intermediate fertilization intensities. Mowing once a year increased seed rain density, whereas it decreased at higher mowing frequencies. Grazing intensity reduced overall seed density and richness by reducing grass seed density, while forb seed density remained unaffected.

Synthesis: Land-use intensity and aboveground productivity significantly influence the species composition and seed densities in the seed rain of temperate agricultural grasslands. Higher land-use intensity and productivity increased seed production but reduced taxonomic and functional diversity in seed rain and may negatively impact ecosystem stability and resilience.
Metagenomics-Toolkit: The Flexible and Efficient Cloud-Based Metagenomics Workflow featuring Machine Learning-Enabled Resource Allocation
Authors: Belmann Peter , Osterholz Benedikt , Kleinboelting Nils , Puehler Alfred , Schlueter Andreas , Sczyrba Alexander
Published: October 2024

The metagenome analysis of complex environments with thousands of datasets, such as those available in the Sequence Read Archive, requires immense computational resources to complete the computational work within an acceptable time frame. Such large-scale analyses require that the underlying infrastructure is used efficiently. In addition, any analysis should be fully reproducible and the workflow must be publicly available to allow other researchers to understand the reasoning behind computed results. Here, we introduce the Metagenomics-Toolkit, a scalable, data agnostic workflow that automates the analysis of short and long metagenomic reads obtained from Illumina or Oxford Nanopore Technology devices, respectively. The Metagenomics-Toolkit offers not only standard features expected in a metagenome workflow, such as quality control, assembly, binning, and annotation, but also distinctive features, such as plasmid identification based on various tools, the recovery of unassembled microbial community members and the discovery of microbial interdependencies through a combination of dereplication, co-occurrence, and genome-scale metabolic modeling. Furthermore, the Metagenomics-Toolkit includes a machine learning-optimized assembly step that tailors the peak RAM value requested by a metagenome assembler to match actual requirements, thereby minimizing the dependency on dedicated high-memory hardware. While the Metagenomics Toolkit can be executed on user workstations, it also offers several optimizations for an efficient cloud-based cluster execution. We compare the Metagenomics-Toolkit to five commonly used metagenomics workflows and demonstrate the capabilities of the Metagenomics-Toolkit by executing it on 757 metagenome datasets from sewage samples for an investigation of a possible sewage core microbiome. The Metagenomics-Toolkit is open source and available at https://github.com/metagenomics/metagenomics-tk.
AMPK activation promotes transcriptional activation of TFEB through its dephosphorylation
Authors: Negoita Florentina , Bringas Conchita Fraguas , Hellberg Kristina , Luda Katarzyna M. , Liu Hongling , Cuenco Joyceline , Zhao Jin-Feng , Sathe Gajanan , Sapkota Gopal , Sakamoto Kei
Published: October 2024

Transcription Factor EB (TFEB) is a critical regulator of lysosomal biogenesis, autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were essential for transcriptional activation of TFEB. In sharp contrast to this proposition, here we demonstrate that AMPK activation leads to dephosphorylation of the C-terminal sites, and that AMPK is dispensable for mTORC1-mediated/torin1-sensitive TFEB activation. We show that a synthetic peptide encompassing C-terminal serine residues of TFEB is a poor substrate of AMPK. Treatment of cells with AMPK activator (MK-8722) or mTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at mTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722-but not torin1-induced dephosphorylation and induction of the vast majority of TFEB target genes.
Genome-wide variant analysis reveals divergent genetic signatures inAedes aegyptiand its morphological variantAedes aegyptivar.luciensis
Authors: Gupta Bhavna , Pandiyan G Navaneetha , Sumitha Melveettil Kishor , Paramasivan Rajaiah , Kalimuthu Mariapillai
Published: October 2024

In this study, we analysed the genetic diversity between the two morphotypes ofAedes aegyptiby identifying and characterizing genomic variants from low-coverage resequencing data. Four samples from each morphotype were sequenced, and high-quality variants were identified. Variants from the four samples of each morphotype were combined, considering only those present in all samples (missing variants were excluded). This resulted in 7,181 variants in the normal type and 4,513 in the variant type, with only 1,180 shared variants identified between the two morphotypes. Most variants in both types were found in non-coding regions. Chromosomal distribution showed comparable variant frequencies between morphotypes, with similar transition/transversion ratios. The neighbor-joining tree indicated distinct genetic clusters for each morphotype, likely driven by different demographic histories. We have not obtained much data on variations in the coding regions, probably due to low sequencing coverage. However, the significant genetic differentiation between the two morphotypes indicates important evolutionary processes at play. Understanding these variations is crucial from an epidemiological perspective, as they may lead to differences in vector competence for pathogens, potentially affecting transmission dynamics and disease risk.
Unraveling the diversity of protein-carbohydrate interfaces: insights from a multi-scale study
Authors: Gheeraert Aria , Guyon Frédéric , Pérez Serge , Galochkina Tatiana
Published: October 2024

Protein-carbohydrate interactions play a crucial role in numerous fundamental biological processes. Thus, description and comparison of the carbohydrate binding site (CBS) architecture is of great importance for understanding of the underlying biological mechanisms. However, traditional approaches for carbohydrate-binding protein analysis and annotation rely primarily on the sequence-based methods applied to specific protein classes. The recently released DIONYSUS database aims to fill this gap by providing tools for CBS comparison at different levels: both in terms of protein properties and classification, as well as in terms of atomistic CBS organization. In the current study, we explore DIONYSUS content using a combination of the suggested approaches in order to evaluate the diversity of the currently resolved non-covalent protein-carbohydrate interfaces at different scales. Notably, our analysis reveals evolutionary convergence of CBS in proteins with distinct folds and coming from organisms across different kingdoms of life. Furthermore, we demonstrate that a CBS structure based approach has the potential to facilitate functional annotation for the proteins with missing information in the existing databases. In particular, it provides reliable information for numerous carbohydrate-binding proteins from rapidly evolving organisms, whose analysis is particularly challenging for classical sequence-based methods.
Mechanoreceptors initiate innate immunity in response to microbial infections
Authors: Stucchi Giulia , Marongiu Laura , Rocca Giuseppe , Galli Marco , Celant Anna , Cozzi Stefano , Polissi Alessandra , Martorana Alessandra Maria , Vai Marina , Orlandi Ivan , Innocenti Metello , Granucci Francesca
Published: October 2024

How mammals mount an effective immune response against infectious agents remains an unresolved fundamental issue in biology. Here, we discovered an unforeseen two-tier mechanism of neutrophil recruitment during infections, in which mechanosensing is key to initiating innate immunity. Leveraging a skin infection model and pathogenic bacteria and fungi, we demonstrate that the early recruitment of neutrophils is mainly danger-driven and partly reminiscent of sterile inflammation. Mechanistically, neutrophil recruitment is initiated by a mechanosensor-dependent pathway, involving the activation of PIEZO1 channels. This leads to LTB4production, which, along with IL-1⍺, induces the release of CXCL1, promoting neutrophil arrival to the site of infection. In contrast, later neutrophil recruitment is TLR- and CXCL2-dependent, highlighting a shift towards a pathogen-driven response to sustain inflammation. These findings advance our understanding of innate immunity by uncovering that mechanical and biochemical signals integrate into a circuit that initiates innate immune responses to microbial infections.