bluuebunny/crossref_metadata_2025 huggingface dataset:
Tularemia in Pediatric Patients: A Case Series and Review of the Literature
Authors: Kossadoum Remadji Fiona , Baron Audrey , Parizot Marie , Husain Maya , Poey Nora , Maurin Max , Caspar Yvan , Caseris Marion , Bidet Philippe , Bonacorsi Stephane
Published: September 2024

Background:

Unfamiliar to pediatricians, tularemia can lead to delays in diagnosis and hinder appropriate treatment, as its clinical presentation often shares similarities with other more prevalent causes of lymphadenopathy diseases in children. We conducted a comprehensive literature review to offer contemporary insights into the clinical manifestations and treatment strategies for tularemia infection in children.

Methods:

Three cases of glandular tularemia were diagnosed in the Pediatric Robert Debré Hospital (Paris) between October 2020 and February 2022. In addition, we conducted a literature search using PubMed in December 2023 of cases of tularemia in children published in English.

Results:

The 94 cases of the literature review highlight the large age range (from 6 weeks to 17 years) and multiple sources of infection, including diverse zoonotic transmission (86.7%) and contact with contaminated water (13.3%). Fever was a consistent symptom. Ulceroglandular (46.7%), glandular (17%) and oropharyngeal forms (18.1%) predominated. The most frequently used diagnostic method was serology (60.6%). The median time to diagnosis for tularemia was 23.5 days. Hospitalization was required in 63.2% of cases, with a median duration of 4 days. Targeted treatment was based on aminoglycosides (37.6%), fluoroquinolones (30.6%) or tetracyclines (12.9%), in accordance with WHO recommendations, with a mainly favorable outcome, although several cases of meningitis were observed.

Conclusion:

Pediatricians should be aware of the etiology of this febrile lymphadenopathy, notably when experiencing beta-lactam treatment failure, even in young infants, which could help reduce the extra costs associated with inappropriate antibiotic use and hospitalization.
The Association Between Pulmonary Vascular Resistance and Posttransplant Outcomes Differs by Left Ventricular Assist Device Status
Authors: Gulati Gaurav , Tsoi Melissa R. , Upshaw Jenica N. , Vest Amanda R. , DeNofrio David , Kiernan Michael S.
Published: September 2024

Elevated pulmonary vascular resistance (PVR) is a risk factor for mortality after heart transplantation (HT), but whether this association differs for patients with and without left ventricular assist device (LVAD) support before HT is unknown. We analyzed adult first-time HT recipients from the United Network for Organ Sharing (UNOS) registry transplanted between 2010 and 2021. We quantified the association between PVR and the outcomes of 30 day graft failure and 1 year mortality using multivariable logistic regression, stratified by LVAD support status at the time of HT. Pulmonary vascular resistance was modeled using restricted cubic splines to identify clinically relevant risk thresholds. We also examined the association with 10 year survival using multivariable Cox proportional hazards regression. For PVR values less than approximately 2 WU, higher PVR was independently associated with a higher risk of early graft failure (odds ratio [OR] = 1.58, 95% CI: 1.06–2.36) and a higher risk of 1 year mortality (OR = 1.32, 95% CI: 1.10–1.59) among LVAD patients only (interaction p = 0.023 and 0.03, respectively). However, for patients surviving at least 1 year, PVR was not associated with long-term mortality among either subgroup. Whether more aggressive reduction of PVR among HT candidates supported with LVADs can mitigate these risks requires further study.
Need for neurorehabilitation in the Middle East and North Africa from 1990 to 2021: an analysis based on the global burden of disease study
Authors: Hedayati Fatemeh , Montazeri Alireza , Sharifi Sarasyabi Mohammad , Darijani Seyed R. , Kayyal Managol , Nakhostin-Ansari Amin , Seyedmirzaei Homa
Published: September 2024

Background:

This study will present the burden of diseases needing neurorehabilitation in Middle East and North Africa (MENA) countries and describe their epidemiology across age and sex groups.

Materials and methods:

This study was conducted based on the Global Burden of Disease (GBD) 2021 findings. The authors used years of healthy life lost due to disability (YLD) as a proxy for the need for neurorehabilitation, and extracted the YLD rates and counts for neonatal encephalopathy due to birth asphyxia and trauma, stroke, neural tube defects, Parkinson’s disease (PD), motor neuron disease, multiple sclerosis (MS), tension-type headache, other neurological disorders (except migraine, dementia, and epilepsy), head injuries, spinal injuries, nerve injury, and asphyxiation across age groups, sexes, and MENA countries.

Results:

YLD rates of disorders needing neurorehabilitation in 1990 and 2021 were 408.08 and 496.19 per 100 000 people, respectively, indicating a 21.59% rise in YLD. Stroke had the highest YLD rates in both 1990 (150.19 per 100 000) and 2021 (192.75 per 100 000). Syria, Saudi Arabia, and the United Arab Emirates had the highest YLD rates for conditions needing neurorehabilitation

Conclusions:

Considering the growing demand for neurorehabilitation with the aging of populations and the historical shortage of rehabilitation services in the region, the gap between the demand and supply may further increase in the coming years, leading to consequences for people living with neurological conditions in the region.
Enhanced Preoperative Planning for Intracranial Aneurysms Through Multimodal Image Fusion of Silent/Time-of-Magnetic Resonance Angiography and Computed Tomography Using 3DSlicer
Authors: Hou Xiaolin , Wu Tao , Li Dingjun , Yao Yuan , Zeng Lin
Published: September 2024

Objective:

This study evaluates the effectiveness of multimodal image fusion (MIF) using silent and time-of-flight (TOF) magnetic resonance angiography (MRA) and computed tomography (CT) for preoperative planning in patients with intracranial aneurysms who have contraindications to contrast media.

Materials and Methods:

A retrospective study included 40 patients with intracranial aneurysms, diagnosed using three-dimensional computed tomography angiography (CTA). These patients underwent both Silent and TOF MRA scans, followed by a CTA scan. The multi-image fusion (MIF) technique, applied using 3DSlicer software, integrated the silent/TOF-MRA with CT images for preoperative assessment. This study compared the image quality, aneurysm detection sensitivity, and anatomic accuracy of the MIF images with those of three-dimensional CTA.

Results:

Silent-MRA-CT fusion images demonstrated higher sensitivity (95.5%) and lower false negative rates (4.5%) compared with TOF-MRA-CT. Furthermore, silent-MRA-CT fusion images outperformed TOF-MRA-CT in terms of signal homogeneity, venous signal interference suppression, and aneurysm visibility (all P < 0.05). The interclass correlation coefficient and kappa values for aneurysm morphology and shape indicated superior measurement consistency and shape concordance of silent-MRA-CT with CTA compared with TOF-MRA-CT (all P < 0.01).

Conclusion:

This study supports the use of silent/TOF-MRA-CT fusion imaging as a reliable alternative to CTA, noting that silent-MRA-CT closely mirrors CTA. Contrast-free MRA-CT fusion images have the potential to be used for preoperative planning in patients with intracranial aneurysms who have contraindications to contrast.
Immunoprevention Strategies for Colorectal Cancer in Lynch Syndrome Carriers
Authors: Bowen Charles M. , Sinha Krishna M. , Vilar Eduardo
Published: September 2024

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce long-term antitumor immunity.
What to Eat for Cancer Prevention
Authors: Zhang Yiwen , Giovannucci Edward L.
Published: September 2024

Over the past 2 decades, the search for dietary factors for developing cancer prevention guidelines has led to a significant expansion in the study of dietary patterns and their relation to cancer. Dietary patterns, which consider the types, amounts, variety, and combination of consumed foods, may encompass additive, synergistic, or interactive effects on human health, compared with individual nutrients or foods. In this review, we discuss the history and methodologies of dietary pattern research, describe common dietary indices used in cancer research, and summarize the existing evidence on dietary patterns and cancer risk. Current evidence supports the beneficial role of dietary patterns that are rich in vegetables, legumes, whole fruit, and whole grains and limited in added sugars, refined grains, processed foods, and red and processed meat in preventing various cancers, including breast, colorectal, and prostate cancers. Additionally, emerging evidence suggests that dietary patterns based on biological mechanisms, such as hyperinsulinemic diet and inflammatory diet, hold promise and may be priority areas for future research.
Repurposing Drugs for Cancer Prevention
Authors: Choradia Nirmal , Szabo Eva
Published: September 2024

The development of agents for cancer prevention is a lengthy process requiring a delicate balance between the safety and tolerability of potential interventions and effectiveness in preventing future cancer. Individuals at risk for a specific cancer are frequently at risk for multiple types of cancer as well as other chronic diseases, especially ones associated with aging. Shared environmental exposures, genetic predisposition, metabolic factors, and commonalities in pathogenesis suggest opportunities for combined targeting of cancer and other chronic diseases. Examples discussed here include mechanisms shared between various cancers and obesity, diabetes, and cardiovascular disease.
Characteristics of High-Quality Multi-Hospital Health Systems Performing Major Cancer Surgery
Authors: Schaefer Sara L. , Kalata Stanley , Nuliyalu Ushapoorna , Ibrahim Andrew M. , Nathan Hari
Published: September 2024

Objective:

To identify characteristics associated with high- and low-quality multi-hospital systems for major cancer surgery

Background:

Although multi-hospital health systems provide most inpatient healthcare in the US, our understanding of how these systems can optimize surgical quality among their hospitals remains limited. Identifying the structural characteristics (e.g., number of hospitals, procedural volume, geographic dispersion) that distinguish high- and low-quality systems may inform actionable strategies to improve surgical quality.

Methods:

We conducted a retrospective cross-sectional observational study of 270,491 Medicare beneficiaries (2016-2020) undergoing major cancer surgery at a multi-hospital health system. Systems were classified into quartiles of quality based on risk- and reliability-adjusted rates of 30-day mortality using a hierarchical multivariable logistical regression model to adjust for patient, procedural, and hospital factors.

Results:

The adjusted 30-day operative mortality rate in the highest- versus lowest-quality quartile of systems was 1.7% versus 3.1%,(P<0.001). High-quality systems had fewer hospitals per system (median [IQR], number of system hospitals, 5 [3-11] vs. 12 [8-30];P<0.001), with each performing more procedures per hospital (median [IQR] annual procedure volume, 104 [52-218] vs. 45 [22-90];P<0.001). High-quality systems were also more geographically concentrated (median [IQR] maximum distance between hospitals, 62 [19-194] vs. 321 [91-1125] miles;P<0.001). Furthermore, high-quality systems demonstrated less variation in quality between hospitals (mean [SD] within-system absolute variation in mortality, 0.8% [0.3%] vs. 2.6% [1.0%];P<0.001).

Conclusions:

The highest-quality multi-hospital systems had fewer, more geographically concentrated hospitals, with each performing more procedures per hospital. Among the highest-quality systems, diverse system phenotypes were represented, suggesting the potential to overcome structural limitations and achieve high quality.
Temporal dynamic alterations of regional homogeneity in major depressive disorder: a study integrating machine learning
Authors: Wu Xiaofeng , Shen Xiaojun , Li Qinghe , Wang Peiyuan
Published: September 2024

Previous studies have found alterations in the local regional homogeneity of brain activity in individuals diagnosed with major depressive disorder. However, many studies have failed to consider that even during resting states, brain activity is dynamic and time-varying. The lack of investigation into the dynamic regional homogeneity has hindered the discovery of biomarkers for depression. This study aimed to assess the utility of the dynamic regional homogeneity by a machine learning model (support vector machine). Sixty-five individuals with dynamic regional homogeneity and 57 healthy controls participated in resting-state functional magnetic resonance rescanning and scale estimating. The dynamic regional homogeneity and receiver operating characteristic curve methods were used for analysis of the imaging data. Relative to healthy controls, major depressive disorder patients displayed increased dynamic regional homogeneity values in the left precuneus and right postcentral gyrus. Additionally, receiver operating characteristic curve results of the dynamic regional homogeneity values in the left precuneus and right postcentral gyrus could distinguish major depressive disorder patients from healthy controls; furthermore, changes in the dynamic regional homogeneity were correlated with depression severity.
Review of Medical Adhesive Technology in the Context of Medical Adhesive-Related Skin Injury
Authors: Holm David , Schommer Kimberly , Kottner Jan
Published: September 2024

In clinical practice, a large variety of medical devices adhere to skin to perform their function. The repeated application and removal of these devices can lead to skin damage or medical adhesive-related skin injury. Awareness of this problem has increased in the past decade, and this adverse event can be prevented with appropriate selection of adhesive products and the appropriate techniques for application and removal. A wide variety of adhesives and backing systems have been developed to create medical devices with an array of attributes, so they can accomplish many different indications in the clinical setting and meet various needs, including doing the clinical job without damaging the skin and causing further patient complications. The selection of an adhesive product should take into consideration a patient’s skin assessment and history of medical adhesive-related skin injury, and using only the minimal adhesive strength needed to perform the function while protecting the skin from damage.
Mark Warner. 26 January 1952—24 December 2021
Authors: Terentjev Eugene , Jardine-Wright Lisa
Published: September 2024

Mark Warner was a prominent theoretical physicist working in the field of soft-matter and polymer science. He was a pioneer in discovering liquid crystalline elastomers as a concept and was the key figure in establishing this subject as a thriving area of research and development. The idea of a material that couples the entropic rubber elasticity with the orientational order of network elements was a complete novelty and a surprise to many. Largely driven by Mark's efforts, this concept, stemming from the coupled order parameters, has been now recognized as a universal phenomenon in several fields: from martensitic transition in shape-memory alloys to engineering and applied mathematics of quasi-convexification. ‘Liquid crystalline elastomers’ will firmly remain as his lasting legacy in science. Mark also made major contributions to physics education, his final legacy being to co-found the national physics education programme, Isaac Physics, in 2013. The ideology of the programme focuses uniquely on students ‘learning by doing’—reassuring students that making mistakes and trying again are fundamental and crucial for learning and developing confidence. Isaac Physics has demonstrated quantifiable impact in raising the aspirations and attainment of hundreds of thousands of students since its inception.
Endel Tulving. 26 May 1927—11 September 2023
Authors: Craik FRS Fergus I. M.
Published: September 2024

Endel Tulving was an Estonian–Canadian cognitive psychologist and cognitive neuroscientist who transformed the study of human memory in the 50 years between 1960 and 2010. He was born in Estonia in 1927, and spent several years in post-war Europe before emigrating to Canada in the late 1940s. He obtained degrees at the University of Toronto and at Harvard University before returning to the University of Toronto as a faculty member in 1956. He was always an independent thinker, and rejected the dominant view of memory and learning in terms of associations in favour of a more cognitive approach in which the organization of remembered events played a major part. He also developed theories on how events are encoded and retrieved, first in terms of behaviour and then in terms of their underlying neural correlates in specific brain regions. His theoretical ideas on different memory systems and their relations to different types of consciousness, laid out in his 1983 book
Elements of episodic memory
(Oxford University Press), continue to play a major part in current work on human memory. As a person, he retained a somewhat European sense of propriety and formality, which often made him seem quite formidable to new acquaintances. Once someone's scientific seriousness was established, however, Endel was warmly supportive of his students and colleagues. He was much loved by his family, and held in high esteem by his fellow scientists.
Culture Harder: Use more specimen to increase MRSA culture yield relative to PCR
Authors: Mitchell Arvette E. , Patel Arpit P. , DiCandilo Jennifer , Rebollido Zachary W. , Pettengill Matthew A.
Published: September 2024

Methicillin-resistant Staphylococcus aureus (MRSA) causes considerable morbidity and mortality in both community acquired and healthcare associated infections, but detecting colonization with MRSA has been shown to improve patient outcomes in certain clinical settings. MRSA colonization detection has been carried out in a variety of ways with molecular assays having superior sensitivity in most studies relative to culture, but culture is disadvantaged in some comparisons by utilization of low specimen volumes. We compared a commercial molecular assay to both low volume (10 µL) and high volume (650 µL) culture and found that increasing the volume utilized for culture led to detection of 25% more cases than low volume culture.
Angiotensin-converting enzyme inhibition and Alzheimer’s disease: Findings from proteome-wide Mendelian randomization and a large prospective cohort study
Authors: Huang Peiyuan , Tang Haibo , Feng Zeying , Stergiakouli Evie , Gaunt Tom R , Zheng Jie , Lu Yao
Published: September 2024

Background

We aimed to provide clinically translatable insights for drug discovery, repurposing, and vigilance for preventing Alzheimer’s disease (AD) by integrating genetic and “real-world” drug use data.

Methods

Proteome-wide Mendelian randomization (MR) analysis was conducted to identify plasma proteins causally related to AD risk using the largest summary-level data to date, followed by colocalization and multi-omic validation analyses (on the gene expression, alternative splicing, and DNA methylation levels in blood and brain, respectively) to prioritize potential druggable targets. We also replicated our MR findings using additional genetic data and, where appropriate, performed multivariable MR for the prioritized findings. Conventional observational analysis using the data from UK Biobank, a large prospective cohort, was performed to provide further clinical implications for our genetic findings.

Results

MR analysis identified 15 plasma proteins with putative causal effects on AD risk. Of them, inhibition of angiotensin-converting enzyme (ACE) was found to increase the risk of AD (OR 1.10, 95% CI 1.08-1.14), which was likely independent of blood pressure as suggested by multivariable MR. Observational analysis in UK Biobank showed a higher incidence (HR 1.24, 95% CI 1.01-1.52) of AD among regular users of ACE inhibitors (ACEI), compared with the counterpart angiotensin receptor blocker users.

Conclusions

In addition to expanding the understanding of druggable targets for AD prevention, our findings highlighted the potential risk of AD associated with the use of ACEIs, a widely prescribed antihypertensive medication, suggesting the need for caution in clinical practice and further research on the effect of antihypertensives on neurodegenerative diseases.
Rigorous (in)validation of ecological models
Authors: Song Chuliang , Levine Jonathan M.
Published: September 2024

The complexity of ecosystems poses a formidable challenge for confidently invalidating ecological models, as current practices struggle to distinguish model inadequacies from the confounding effects of unobserved biotic or abiotic factors. The prevailing inability to falsify models has resulted in an accumulation of models but not an accumulation of confidence. Here, we introduce a new approach rooted in queueing theory, termed thecovariance criteria, that establishes a rigorous test for model validity based on covariance relationships between observable quantities. These criteria set a high bar for models to pass by specifying necessary conditions that must hold regardless of unobserved factors. We demonstrate the broad applicability and discriminatory power of the covariance criteria by applying them to three long-standing challenges in ecological theory: resolving competing models of predator-prey functional responses, disentangling ecological and evolutionary dynamics in systems with rapid evolution, and detecting the often-elusive influence of higher-order species interactions. Across these diverse case studies, the covariance criteria consistently rule out inadequate models, while building strong confidence in those that provide strategically useful approximations. The covariance criteria approach is mathematically rigorous, computationally efficient, and often non-parametric, making it immediately applicable to existing data and models.
The use of 3D-printers as plotters opens up a new world in performing 2D migration analyses
Authors: Köppe Hanjo , Richert Magnus G. , Singer Debora , Köppe Jorn , Köppe Mattes , Tzvetkov Mladen , Schroeder Henry W. S. , Bekeschus Sander , Bien-Möller Sandra
Published: September 2024

Scratch wound healing assays remain one of the most commonly used 2D migration assay to obtain a broad overview of the migration behavior of cultured cells. They are easy to perform and cost effective, but yet not standardized in terms of the geometric dimensions of the scratch, e.g. consistency of the scratch width and straightness of the line, especially when performed manually. Furthermore, conventional scratch assays only include a single scratch, which leads to a limited evaluation of a restricted cell population within the culture plates, but not of all cells grown in the chamber. There are commercially available ‘scratch-makers’ which are highly expensive and yet lack advanced functions such as scratching complex patterns. However, such complex scratch formations would make it possible to assess the entire cell population in a chamber and to evaluate the influence of the scratch itself, e.g. with regard to the regulation of migration-associated proteins. We have therefore developed for the first time a method that not only standardizes the scratch dimensions for different pipette tips, but also gives the opportunity to scratch any conceivable 2D shape by using 3D printers as 2D plotters. This open-source and low-cost system can be performed with any plate format from any manufacture under culture hood conditions. The 2D plotter-based method developed and validated by us provides highly reproducible and consistent scratch parameters forin vitromigration analyses.
IgGM: A Generative Model for Functional Antibody and Nanobody Design
Authors: Wang Rubo , Wu Fandi , Gao Xingyu , Wu Jiaxiang , Zhao Peilin , Yao Jianhua
Published: September 2024

Abstract

Immunoglobulins are crucial proteins produced by the immune system to identify and bind to foreign substances, playing an essential role in shielding organisms from infections and diseases. Designing specific antibodies opens new pathways for disease treatment. With the rise of deep learning, AI-driven drug design has become possible, leading to several methods for antibody design. However, many of these approaches require additional conditions that differ from real-world scenarios, making it challenging to incorporate them into existing antibody design processes. Here, we introduce IgGM, a generative model for the de novo design of immunoglobulins with functional specificity. IgGM produces antibody sequences and structures simultaneously for a given antigen, consisting of three core components: a pre-trained language model for extracting sequence features, a feature learning module for identifying pertinent features, and a prediction module that outputs designed antibody sequences and the predicted complete antibody-antigen complex structure. IgGM has demonstrated its effectiveness in not only predicting structures but also designing novel antibodies and nanobodies. This makes it highly applicable in a wide range of practical situations related to antibody and nanobody design.1
Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens
Authors: Fischer Jonas , Shutta Katherine H. , Chen Chen , Fanfani Viola , Saha Enakshi , Mandros Panagiotis , Ben Guebila Marouen , Xiu Joanne , Nieva Jorge , Liu Stephen , Uprety Dipesh , Spetzler David , Lopes-Ramos Camila M. , DeMeo Dawn , Quackenbush John
Published: September 2024

There is increasing recognition that the sex chromosomes, X and Y, play an important role in health and disease that goes beyond the determination of biological sex. Loss of the Y chromosome (LOY) in blood, which occurs naturally in aging men, has been found to be a driver of cardiac fibrosis and heart failure mortality. LOY also occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We analyzed LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data and found evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion. Analyzing immunotherapy data, we show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome, providing a new and powerful biomarker for predicting immunotherapy response in LUAD tumors in males.
Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer’s disease
Authors: Babygirija Reji , Han Jessica H. , Sonsalla Michelle M. , Matoska Ryan , Calubag Mariah F. , Green Cara L. , Tobon Anna , Yeh Chung-Yang , Vertein Diana , Schlorf Sophia , Illiano Julia , Liu Yang , Grunow Isaac , Rigby Michael J. , Puglielli Luigi , Harris David A. , Denu John M. , Lamming Dudley W.
Published: September 2024

Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimer’s disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce Aβ plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.
Loss of PMR4 callose synthase results in salicylic acid-independent and broad-spectrum resistance to clubroot inArabidopsisandBrassica napus
Authors: Luo Brian , Wang Lipu , Wen Rui , Yang Kun , Liu Xunjia , Tu Jiangying , Dumonceaux Tim , Wei Yangdou , Peng Garry , Xiao Wei
Published: September 2024

The clubroot disease caused by protistPlasmodiophora brassicaeis one of the most important diseases of Brassica crops. Growing clubroot-resistant cultivars remains the most effective and practical approach to managing clubroot disease. However, resistance gene-mediated immunity is rapidly overcome in the field when new pathotypes arise. In this study, we identifiedPMR4as a potential gene target for creating a novel clubroot-resistant source. RecessivePMR4mutations inArabidopsis thalianaconferred broad-spectrum resistance to multipleP. brassicaepathotypes, independent of salicylic acid-mediated plant immunity. CRISPR/Cas9-mediated gene-editing was employed to create mutations in twoPMR4orthologs in theB. napusgenome, and resulting homozygous mutants exhibited dual resistance to powdery mildew and clubroot. PMR4 is required for the callose deposition at wound and powdery mildew infection sites in leaves. This study reveals that callose deposition in roots is induced byP. brassicaeinfection and requires PMR4. It appears that the clubroot disease progression is arrested at the primary-to-secondary infection phase inpmr4-1mutants. Together, this study demonstrates thatPMR4-encoded callose synthase is a host susceptibility factor required forP. brassicaeto complete its life cycle, and thatPMR4can be targeted against both powdery mildew and clubroot diseases in Brassica crops.
miR-21: A therapeutic target for delaying severe liver disease and hepatocellular carcinoma in high-fat-diet-fed mice
Authors: Jagtap Urmila , Quan Anan , Ono Yuho , Lee Jonathan , Shen Kylie A. , Manakov Sergei , Szabo Gyongyi , Nasser Imad , Slack Frank J.
Published: September 2024

Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targetsTransforming growth factor beta-induced(Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis,Tgfbiexpression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.

Significance

Our study demonstrates in vivo that miR-21 has protective functions in the broad spectrum of high-fat diet-based, progressive liver disease and cancer, and we show potential therapeutic value of a microRNA-21 mimic.

Graphical abstract
How interactions between temperature and resources scale from populations to communities
Authors: Kremer Colin T. , Thomas Mridul K. , Klausmeier Christopher A. , Litchman Elena
Published: September 2024

Temperature and resources are fundamental factors that determine the ability of organisms to function and survive, while influencing their development, growth, and reproduction. Major bodies of ecological theory have emerged, largely independently, to address temperature and resource effects. It remains a major challenge to unite these ideas and determine the interactive effects of temperature and resources on ecological patterns and processes, and their consequences across ecological scales. Here, we propose a simple, physiologically motivated model capturing the interactive effects of temperature and resources (including inorganic nutrients and light) on the growth of microbial ectotherms over multiple ecological scales. From this model we derive a set of key predictions. At the population level, we predict (i) interactive effects of resource limitation on thermal traits, (ii) consistent differences in the temperature sensitivity of auto- and heterotrophs, and (iii) the existence of specific tradeoffs between traits that determine the shape of thermal performance curves. At the community level, we derive predictions for (iv) how limitation by nutrients and light can change the relationship between temperature and productivity. All four predictions are upheld, based on our analyses of a large compilation of laboratory data on microbial growth, as well as field experiments with marine phytoplankton communities. Collectively, our modeling framework provides a new way of thinking about the interplay between two fundamental aspects of life — temperature and resources — and how they constrain and structure ecological properties across scales. Providing links between population and community responses to simultaneous changes in abiotic factors is essential to anticipating the multifaceted effects of global change.
A novel OsIAA3-OsARF16-OsBUL1module regulates grain size in rice
Authors: Xian Fengjun , Liu Shuya , Huang Jishuai , Xie Bin , Zhu Lin , Zhang Qiannan , Lv Chen , Xu Yimeng , Zhang Xinrong , Hu Jun
Published: September 2024

Auxin plays an important role in almost every aspect of plant growth and development. However, the molecular mechanism underlying the control of grain size via auxin signaling pathways is still obscure. Here, we reported that the riceAux/IAAgeneOsIAA3positively regulates grain size by promoting the cell expansion and proliferation of spikelet hulls. OsIAA3 interacted with 11 OsARFs, among which the interaction with OsARF16 was the strongest. Knockout ofosarf16led to smaller grain with decreased grain length, grain width, grain thickness and 1,000-grain weight. Meanwhile, transgenic plants overexpressingOsARF16produced apparently bigger grain with increased grain length and 1,000-grain weight. Additionally,OsBUL1, which positive regulates grain size by promoting cell expansion is a direct target gene ofOsARF16. Results demonstrated that the interaction between OsIAA3 and OsARF16 repressed the transcriptional activation of OsARF16 onOsBUL1. Taken together, our study revealed a novel OsIAA3-OsARF16-OsBUL1module which regulates grain size, enriching the molecular mechanism of auxin signaling pathway involved in regulating grain size.
A Paradoxical Tumor Antigen Specific Response in the Liver
Authors: Trehan Rajiv , Zhu Xiao Bin , Huang Patrick , Wang Xin , Soliman Marlaine , Strepay Dillon , Nur Amran , Kedei Noemi , Arhin Martin , Ghabra Shadin , Rodríguez-Matos Francisco , Benmebarek Mohamed-Reda , Ma Chi , Korangy Firouzeh , Greten Tim F.
Published: September 2024

Functional tumor-specific CD8+ T cells are essential for an effective anti-tumor immune response and the efficacy of immune checkpoint inhibitor therapy. In comparison to other organ sites, we found higher numbers of tumor-specific CD8+ T cells in primary, metastatic liver tumors in murine tumor models. Despite their abundance, CD8+ T cells in the liver displayed an exhausted phenotype. Depletion of CD8+ T cells showed that liver tumor-reactive CD8+ T failed to control liver tumors but was effective against subcutaneous tumors. Similarly, analysis of single-cell RNA sequencing data from patients showed a higher frequency of exhausted tumor-reactive CD8+ T cells in liver metastasis compared to paired primary colon cancer. High-dimensional, multi-omic analysis combining proteomic CODEX and scRNA-seq data revealed enriched interaction of SPP1+ macrophages and CD8+ tumor-reactive T cells in profibrotic, alpha-SMA rich regions in the liver. Liver tumors grew less in Spp1-/-mice and the tumor-specific CD8+ T cells were less exhausted. Differential pseudotime trajectory inference analysis revealed extrahepatic signaling promoting an intermediate cell (IC) population in the liver, characterized by co-expression of VISG4, CSF1R, CD163, TGF-βR, IL-6R, SPP1. scRNA-seq of a third data set of premetastatic adenocarcinoma showed that enrichment of this population may predict liver metastasis. Our data suggests a mechanism by which extrahepatic tumors facilitate the formation of liver metastasis by promoting an IC population inhibiting tumor-reactive CD8+ T cell function.
DiffPaSS – High-performance differentiable pairing of protein sequences using soft scores
Authors: Lupo Umberto , Sgarbossa Damiano , Milighetti Martina , Bitbol Anne-Florence
Published: September 2024

Identifying interacting partners from two sets of protein sequences has important applications in computational biology. Interacting partners share similarities across species due to their common evolutionary history, and feature correlations in amino acid usage due to the need to maintain complementary interaction interfaces. Thus, the problem of finding interacting pairs can be formulated as searching for a pairing of sequences that maximizes a sequence similarity or a coevolution score. Several methods have been developed to address this problem, applying different approximate optimization methods to different scores. We introduce DiffPaSS, a differentiable framework for flexible, fast, and hyperparameter-free optimization for pairing interacting biological sequences, which can be applied to a wide variety of scores. We apply it to a benchmark prokaryotic dataset, using mutual information and neighbor graph alignment scores. DiffPaSS outperforms existing algorithms for optimizing the same scores. We demonstrate the usefulness of our paired alignments for the prediction of protein complex structure. DiffPaSS does not require sequences to be aligned, and we also apply it to non-aligned sequences from T cell receptors.
High WEE1 expression is independently linked to poor survival in multiple myeloma
Authors: Simhal Anish K. , Firestone Ross , Oh Jung Hun , Avutu Viswatej , Norton Larry , Hultcrantz Malin , Usmani Saad Z. , Maclachlan Kylee H. , Deasy Joseph O.
Published: September 2024

Current prognostic scores in multiple myeloma (MM) currently rely on disease burden and a limited set of genomic alterations. Some studies have suggested gene expression panels may predict clinical outcomes, but none are presently utilized in clinical practice. We therefore analyzed the MMRF CoMMpass dataset (N=659) and identified a high-risk group (top tertile) and a low-risk group (bottom tertile) based on WEE1 expression sorted in descending order. The tyrosine kinase WEE1 is a critical cell cycle regulator during the S-phase and G2M-checkpoint. Abnormal WEE1 expression has been implicated in multiple cancers including breast, ovarian, and gastric cancers, but has not until this time been implicated in MM. PFS was significantly different (p <1e-9) between the groups, which was validated in two independent microarray gene expression profiling (GEP) datasets from the Total Therapy 2 (N=341) and 3 (N=214) trials. Our results show WEE1 expression is prognostic independent of known biomarkers, differentiates outcomes associated with known markers, is upregulated independently of its interacting neighbors, and is associated with dysregulated P53 pathways. This suggests that WEE1 expression levels may have clinical utility in prognosticating outcomes in newly diagnosed MM and may support the application of WEE1 inhibitors to MM preclinical models. Determining the causes of abnormal WEE1 expression may uncover novel therapeutic pathways.
Metabolic modeling identifies determinants of thermal growth responses inArabidopsis thaliana
Authors: Wendering Philipp , Andreou Gregory M. , Laitinen Roosa A. E. , Nikoloski Zoran
Published: September 2024

Temperature is a critical environmental factor affecting nearly all plant processes, including growth, development, and yield. Yet, despite decades of research, we lack the ability to predict plant performance at different temperatures, limiting the development of climate-resilient crops. Further, there is a pressing need to bridge the gap between the prediction of physiological and molecular traits to improve our understanding and manipulation of plant temperature responses. Here, we developed the first enzyme-constrained model ofArabidopsis thaliana’s metabolism, facilitating predictions of growth-related phenotypes at different temperatures. We showed that the model can be employed forin silicoidentification of genes that affect plant growth at suboptimal growth temperature. Using mutant lines, we validated the genes predicted to affect plant growth, demonstrating the potential of metabolic modeling in accurately predicting plant thermal responses. The temperature-dependent enzyme-constrained metabolic model provides a template that can be used for developing sophisticated strategies to engineer climate-resilient crops.
PEBP1 amplifies mitochondrial dysfunction induced integrated stress response
Authors: Cheng Ling , Meliala Ian , Kong Yidi , Chen Jingyuan , Proud Christopher G , Björklund Mikael
Published: September 2024

Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing thermal proteome profiling (TPP), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eIF2α phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor kinase (HRI), the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.
Exploring group-specific technical variation patterns of single-cell data
Authors: Zhou Yang , Sheng Qiongyu , Jin Shuilin
Published: September 2024

Constructing single-cell atlases requires preserving differences attributable to biological variables, such as cell types, tissue origins, and disease states, while eliminating batch effects. However, existing methods are inadequate in explicitly modeling these biological variables. Here, we introduce SIGNAL, a general framework designed to disentangle biological and technical effects by learning group-specific technical variation patterns, thereby linking these metadata to data integration. SIGNAL employs a novel variant of principal component analysis (PCA) to align multiple batches, enabling the integration of 1 million cells in approximately 2 minutes. SIGNAL, despite its computational simplicity, surpasses state-of-the-art methods across multiple integration scenarios: (1) heterogeneous datasets, (2) cross-species datasets, (3) simulated datasets, (4) integration on low-quality cell annotations, and (5) reference-based integration. Furthermore, we demonstrate that SIGNAL accurately transfers knowledge from reference to query datasets. Notably, we propose a self-adjustment strategy to restore annotated cell labels potentially distorted during integration. Finally, we apply SIGNAL to multiple large-scale atlases, including a human heart cell atlas containing 2.7 million cells, identifying tissue- and developmental stage-specific subtypes, as well as condition-specific cell states. This underscores SIGNAL’s exceptional capability in multi-scale analysis.
Mitochondrial Transplantation: Adaptive Bio-enhancement
Authors: Lu Xiaomeng
Published: September 2024

Mitochondria, known as the powerhouse of the cell, are essential for cellular energy production. Dysfunction in mitochondrial function can significantly affect various organs. Transplanting healthy mitochondria can enhance the bioenergetics of diseased cells and treat various conditions, yet the limits of mitochondrial transplantation are still unknown. Our study reveals that the source of transplanted mitochondria is not restricted by species, and recipient cells show no significant immune response to mitochondria from different lineages. We also found that metabolic compatibility between the recipient and exogenous mitochondria is crucial, and transplanting mitochondria from different species can endow recipient cells with distinct characteristics to combat diseases. Furthermore, our data indicate that there is competition among mitochondria with varying functions, with more powerful mitochondria yielding better therapeutic effects. Notably, we have not yet found an upper limit for the bioenhancement provided by exogenous mitochondria. Our research proposes a feasible path for human bioenhancement through mitochondrial transplantation: adaptive bioenhancement.