bluuebunny/crossref_metadata_2025 huggingface dataset:
Geriatric Assessment Impairment Profiles and Mortality in Older Adults With Gastrointestinal Cancers: Latent Class Analysis of the CARE Registry
Authors: Thai Sydney T , Lund Jennifer L , Kenzik Kelly M , Poole Charles , Stürmer Til , Buse John B , Harmon Christian A , Al-Obaidi Mustafa , Williams Grant R
Published: December 2023

Background

Many older adults with cancer have ≥2 impairments on geriatric assessment, which affects present and future frailty status, treatment tolerability, and outcomes. Our objective was to identify and describe distinct geriatric assessment impairment classes using latent class analysis (LCA) in older patients with gastrointestinal malignancies and assess 1-year mortality.

Methods

We used the Cancer & Aging Resilience Evaluation (CARE) Study, a registry of older adults (≥60 years) at University of Alabama at Birmingham. The analytic cohort included patients with gastrointestinal malignancies who completed a self-administered geriatric assessment (CARE tool) before chemotherapy and had ≥1 geriatric assessment impairment. Thirteen geriatric assessment impairments were used as indicators in LCA. Resultant classes were described, mortality was estimated, and risk contrasts (differences and hazard ratios) were calculated with 95% confidence intervals. For comparison, estimates were provided for frailty categories (robust, prefrail, and frail) determined from 44 items in the CARE tool. Stratified analyses included high-risk (pancreatic, hepatobiliary, and esophageal) versus low-risk gastrointestinal cancers, and stage (IV vs I–III).

Results

Six geriatric assessment impairment classes were identified: Mild impairment (LC1); Social support impairment (LC2); Weight loss alone (LC3); Impaired, low anxiety/depression (LC4); Impaired with anxiety/depression (LC5); and Global impairment (LC6). One-year mortality was 14%, 22%, 29%, 34%, 50%, and 50% for LC1–LC6, respectively. For frailty categories, estimates ranged from 18% (robust) to 40% (frail). In stratified analyses, LC4–LC6 consistently had higher mortality estimates compared to LC1.

Conclusions

The 6 geriatric assessment impairment classes showed a wider spread of mortality estimates compared to frailty categories and could be used to identify vulnerable patients and to plan interventions.
Timed Activity to Minimize Sleep Disturbance in People With Cognitive Impairment
Authors: Hodgson Nancy A , McPhillips Miranda V , Petrovsky Darina V , Perez Adriana , Talwar Sonia , Gooneratne Nalaka , Riegel Barbara , Aryal Subhash , Gitlin Laura N
Published: December 2023

Background and Objectives

Sleep disturbances occur in >60% of persons living with cognitive impairment, affecting their quality of life (QOL). Regulating the sleep–wake cycle through engaging cognitive, physical, and sensory-based activities delivered at strategic times may reduce sleep disturbances and be a feasible nonpharmacological treatment for sleep problems. The objective of this trial was to test the efficacy of a timed-activity intervention in improving QOL and sleep disturbances in persons living with cognitive impairment.

Research Design and Method

Randomized 2-group parallel design involving 209 dyads of community-residing persons living with cognitive impairment and care partners. Dyads were randomly assigned (1:1) to 1-hr home activity sessions administered weekly in the morning, afternoon, or evening over 4 weeks (the Healthy Patterns Sleep Program), or to an attention-control condition consisting of sleep hygiene training plus education on home safety and health promotion. QOL, objective and subjective sleep quality, and neuropsychiatric symptoms were assessed at baseline and 4 weeks later.

Results

QOL was significantly improved in the intervention group compared to control (p = .0491). There were no significant effects on objective or subjective sleep or neuropsychiatric symptoms. In a subgroup analysis, subjective sleep as measured by the PROMIS (Patient Reported Outcomes Measurement Information System) Sleep-Related Impairment survey was significantly improved in the intervention group compared to the control group for individuals with symptoms of depression (p = .015) or poor observed sleep at baseline (p = .005).

Discussion and Implications

The Healthy Patterns Intervention may benefit QOL for persons living with cognitive impairment and those with poor subjective sleep. A longer dose may be necessary to elicit improvement in actigraphically measured sleep–wake activity.

Clinical Trial Registration Number

NCT0368218 5
Evaluating the incompleteness magnitude using an unbiased estimate of the b value
Authors: Godano C , Petrillo G , Lippiello E
Published: December 2023

The evaluation of the b value of the Gutenberg–Richter (GR) law, for a sample composed of n earthquakes, presents a systematic positive bias δb which is proportional to 1/n . In this study, we show how to incorporate in δb the bias introduced by deviations from the GR law. More precisely we show that δb is proportional to the square of the variability coefficient CV, defined as the ratio between the standard deviation of the magnitude distribution and its mean value. When the magnitude distribution follows the GR law CV = 1 and this allows us to introduce a new graphical procedure, based on the dependence of b on n, which allows us to identify the incompleteness magnitude mc as the threshold magnitude leading to CV = 1. The method is tested on synthetic catalogues and it is applied to estimate mc in Southern California, Japan and New Zealand.
‘How to make a ring jump in the manner of a locust’: recipes to animate small objects in late medieval European manuscripts
Authors: da Silva Baptista Vanessa
Published: December 2023

In his late thirteenth-century collection of playful and amusing recipes, which this article calls magic tricks, Richard de Grimhill, a low-ranking Worcester noble, collected a trick ‘to make a ring jump in the manner of a locust’, alongside other instructions to animate domestic objects such as eggs, loaves of bread and spit-roasting chickens. Using a source base of 100 late medieval manuscripts, this article demonstrates that rings and other domestic objects were animated in various ways: through sleight of hand, by exploiting the chemical properties of mercury, or with a mixture of mercury, sulphur, and saltpetre. Placing these three methods in their manuscript and cultural contexts, I underscore that late medieval European people experienced magic tricks as a form of both cognitive play and playful experimentation with chemical knowledge. They thus have broader implications for late medieval European approaches to the possibilities and limitations of the human mind and physical matter.
Investment Contracts and the Reform of Investment Arbitration: Towards Sustainability
Authors: Faccio Sondra
Published: December 2023

This article aims to contribute to the debate surrounding the reform of international investment law and arbitration, focusing on the role of the investment contract. It will discuss how this instrument can make international investment law and arbitration more balanced, by imposing ad hoc obligations upon the investor to strengthen the sustainability of foreign direct investment (FDI); and by providing for State-investor arbitration in case of breach. The article will also assess how contractual provisions may have the effect of grounding counterclaims by States in investment treaty arbitration, allowing for new avenues for sustainable development in investor-State arbitration.
Pharmacists’ role and experiences with delivering mental health care within team-based primary care settings during the COVID-19 pandemic
Authors: Ashcroft Rachelle , Mathers Annalise , Gin Amanda , Lam Simon , Donnelly Catherine , Brown Judith Belle , Kourgiantakis Toula , Mehta Kavita , Rayner Jennifer , Sur Deepy , Adamson Keith , Kirvan Anne , Dolovich Lisa
Published: December 2023

Objectives

Pharmacists have been increasingly integrated into primary care teams, leading to improved health outcomes for patients. The two objectives of this study were (i) to describe how the COVID-19 pandemic impacted pharmacists’ role in mental health care within Canadian primary care teams and (ii) to describe Canadian pharmacists’ experiences collaborating with other healthcare providers in the delivery of mental health services during the COVID-19 pandemic.

Methods

Cross-sectional observational study utilizing an online survey consisting of closed-ended and open-ended questions. Primary care pharmacists in Ontario were eligible to participate. Descriptive statistics were collated, and qualitative data underwent thematic analysis. A total of 51 pharmacists participated in the study.

Key findings

The COVID-19 pandemic has led to the expanding role of pharmacists in attending to the mental health care of patients. Working within a collaborative, interprofessional healthcare environment, pharmacists support patients’ mental health in a variety of ways, including medication education and management, non-pharmacologic approaches and supportive conversations, and identification of resources, including referrals, wellness checks, and consulting with physicians. Increasing demand for mental health services has led to higher referrals to pharmacists, which will likely persist and require further education of pharmacists in mental health along with better access to deliver virtual care.

Conclusion

In response to the increasing mental health care needs of patients since the COVID-19 pandemic, primary care pharmacists reported increased attention spent on mental health care. Building capacity and ensuring support for pharmacists to continue to address the increasing mental health care demands is essential.
On exponential stability in mean square of nonlinear delay differential equations with Markovian switching
Authors: Quan Tran Ky , Huu Anh Ngoc Pham , Bao Tran Thai , Dinh Huy Nguyen
Published: December 2023

This paper addresses the exponential stability of nonlinear delay differential equations with Markovian switching. Drawing upon the comparison principle, we introduce the explicit criteria for achieving the exponential stability in mean square (sense). These criteria are formulated in terms of the equation coefficients and the generator of the Markovian switching process. As a result, these criteria can be verified without needing to construct the Lyapunov functions, a departure from the conventional approach found in the Razumikhin-type theorems. The paper includes an illustrative example and also demonstrates an application to the switched neural networks.
Long-term Sudan Virus Ebola Survivors Maintain Multiple Antiviral Defense Mechanisms
Authors: Sobarzo Ariel , Moné Yves , Lang Steven , Gelkop Sigal , Brangel Polina , Kuehne Ana I , McKendry Rachel A , Mell Joshua Chang , Ahmed Azad , Davis Claytus , Dye John M , Lutwama Julius Julian , Lobel Leslie , Veas Francisco , Ehrlich Garth D
Published: December 2023

Background

The critical issues of sustained memory immunity following ebolavirus disease among long-term survivors are still unclear.

Methods

Here, we examine virus-specific immune and inflammatory responses following in vitro challengd in 12 Sudan virus (SUDV) long-term survivors from Uganda’s 2000–2001 Gulu outbreak, 15 years after recovery. Total RNA from isolated SUDV-stimulated and unstimulated peripheral blood mononuclear cells was extracted and analyzed. Matched serum samples were also collected to determine SUDV IgG levels and functionality.

Results

We detected persistent humoral (58%, 7 of 12) and cellular (33%, 4 of 12) immune responses in SUDV long-term survivors and identified critical molecular mechanisms of innate and adaptive immunity. Gene expression in immune pathways, the interferon signaling system, antiviral defense response, and activation and regulation of T- and B-cell responses were observed. SUDV long-term survivors also maintained robust virus-specific IgG antibodies capable of polyfunctional responses, including neutralizing and innate Fc effector functions.

Conclusions

Data integration identified significant correlations among humoral and cellular immune responses and pinpointed a specific innate and adaptive gene expression signature associated with long-lasting immunity. This could help identify natural and vaccine correlates of protection against ebolavirus disease.
The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile
Authors: Solís-Barbosa Miguel A , Santana Eduardo , Muñoz-Torres José R , Segovia-Gamboa Norma C , Patiño-Martínez Eduardo , Meraz-Ríos Marco A , Samaniego Rafael , Sánchez-Mateos Paloma , Sánchez-Torres Carmen
Published: December 2023

Nurr1 is a member of the orphan nuclear receptor family NR4A (nuclear receptor subfamily 4 group A) that modulates inflammation in several cell lineages, both positively and negatively. Macrophages are key regulators of inflammatory responses, yet information about the role of Nurr1 in human macrophages is scarce. Here we examined Nurr1 expression and activity in steady state and activated human macrophages. Pro- and anti-inflammatory macrophages were generated in vitro by culture of blood monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Nurr1 expression was predominant in macrophages with the pro-inflammatory phenotype. Nurr1 activation with the agonists 1,1-bis(3ʹ-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) or isoxazolo-pyridinone 7e (IP7e) did not globally modify the polarization status of pro-inflammatory macrophages, but they decreased their production of TNF, IL-1β, IL-6, IL-8, IL-12 p40, CCL2, IFN-β, and reactive oxygen species, with variable potencies. Conversely, Nurr1 deficient macrophages increased the expression of transcripts encoding inflammatory mediators, particularly that of IL6, IFNB1, and CCL2. Mechanistically, endogenous Nurr1 interacted with NF-κB p65 in basal conditions and upon lipopolysaccharide (LPS)-mediated activation. C-DIM12 stabilized those complexes in cells exposed to LPS and concurrently decreased NF-κB transcriptional activity and p65 nuclear translocation. Expression of high levels of Nurr1 was associated with a subset of dermal macrophages that display enhanced levels of TNF and lower expression of the anti-inflammatory marker CD163L1 in skin lesions from patients with bullous pemphigoid (BP), a chronic inflammatory autoimmune blistering disorder. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages, both in vivo and in vitro, where it may constitute a brake to attenuate the synthesis of inflammatory mediators.
Effect of albumin substitution on pharmacokinetics of piperacillin/tazobactam in patients with severe burn injury admitted to the ICU
Authors: Wulkersdorfer Beatrix , Bergmann Felix , Amann Lisa , Fochtmann-Frana Alexandra , Al Jalali Valentin , Kurdina Elizaveta , Lackner Edith , Wicha Sebastian G , Dorn Christoph , Schäfer Bruno , Ihra Gerald , Rath Thomas , Radtke Christine , Zeitlinger Markus
Published: December 2023

Background

Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma.

Patients and methods

Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation.

Results

A total of seven patients with second- to third-degree burns involving 20%–60% of the total body surface were enrolled. Mean (SD) AUC0–8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0–8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively.

Conclusions

Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0–8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding.
Evaluation framework for conversational agents with artificial intelligence in health interventions: a systematic scoping review
Authors: Ding Hang , Simmich Joshua , Vaezipour Atiyeh , Andrews Nicole , Russell Trevor
Published: December 2023

Objectives

Conversational agents (CAs) with emerging artificial intelligence present new opportunities to assist in health interventions but are difficult to evaluate, deterring their applications in the real world. We aimed to synthesize existing evidence and knowledge and outline an evaluation framework for CA interventions.

Materials and Methods

We conducted a systematic scoping review to investigate designs and outcome measures used in the studies that evaluated CAs for health interventions. We then nested the results into an overarching digital health framework proposed by the World Health Organization (WHO).

Results

The review included 81 studies evaluating CAs in experimental (n = 59), observational (n = 15) trials, and other research designs (n = 7). Most studies (n = 72, 89%) were published in the past 5 years. The proposed CA-evaluation framework includes 4 evaluation stages: (1) feasibility/usability, (2) efficacy, (3) effectiveness, and (4) implementation, aligning with WHO’s stepwise evaluation strategy. Across these stages, this article presents the essential evidence of different study designs (n = 8), sample sizes, and main evaluation categories (n = 7) with subcategories (n = 40). The main evaluation categories included (1) functionality, (2) safety and information quality, (3) user experience, (4) clinical and health outcomes, (5) costs and cost benefits, (6) usage, adherence, and uptake, and (7) user characteristics for implementation research. Furthermore, the framework highlighted the essential evaluation areas (potential primary outcomes) and gaps across the evaluation stages.

Discussion and Conclusion

This review presents a new framework with practical design details to support the evaluation of CA interventions in healthcare research.

Protocol registration

The Open Science Framework (https://osf.io/9hq2v) on March 22, 2021.
Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients
Authors: Tateishi Ukihide , Kimura Koichiro , Tsuchiya Junichi , Kano Daisuke , Watabe Tadashi , Nonomura Norio , Saito Katsuhiko , Yokoyama Kota , Yamagiwa Ken , Adachi Takuya , Kojima Yuji , Yoshida Soichiro , Fujii Yasuhisa
Published: December 2023

Objective

18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer.

Methods

Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n = 7) and patients with biochemical recurrence (Cohort 2, n = 3). All subjects received a single dose of 3.7 MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87 ± 1.05 (percentage of injected dose [%ID]/ml) at 5 min and then decreased to 1.60 ± 0.78 in 6 h. The systemic radioactivity reached a maximum of 211.05 ± 6.77 (%ID$\times$103) at 5 min and decreased to 7.18 ± 3.91 in 6 h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were >5 mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60 min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively.

Conclusions

Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.
Effect of ethanol exposure on innate immune response in sepsis
Authors: Roychowdhury Sanjoy , Pant Bishnu , Cross Emily , Scheraga Rachel , Vachharajani Vidula
Published: December 2023

Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
Health-related quality of life with pembrolizumab plus chemotherapy vs placebo plus chemotherapy for advanced triple-negative breast cancer: KEYNOTE-355
Authors: Cescon David W , Schmid Peter , Rugo Hope S , Im Seock-Ah , Md. Yusof Mastura , Gallardo Carlos , Lipatov Oleg , Barrios Carlos H , Perez-Garcia Jose , Iwata Hiroji , Masuda Norikazu , Otero Marco Torregroza , Gokmen Erhan , Loi Sherene , Haiderali Amin , Zhou Xuan , Guo Zifang , Nguyen Allison Martin , Cortes Javier
Published: December 2023

Background

In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355.

Methods

Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator’s choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline.

Results

Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = −1.81, 95% confidence interval [CI] = −6.92 to 3.30), emotional functioning (least-squares mean difference = −1.43, 95% CI = −7.03 to 4.16), physical functioning (least-squares mean difference = −1.05, 95% CI = −6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = −5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning.

Conclusions

Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10).
The journalistic preference for extreme exemplars: educational socialization, psychological biases, or editorial policy?
Authors: Aarøe Lene , Andersen Kim , Skovsgaard Morten , Svith Flemming , Schmøkel Rasmus
Published: December 2023

Exemplars are central in news reporting. However, extreme negative exemplars can bias citizens’ factual perceptions and attributions of political responsibility. Nonetheless, our knowledge of the factors shaping journalistic preferences for including exemplars in news stories is limited. We investigate the extent to which educational socialization, psychological biases, and editorial policy shape journalistic preferences for extreme negative exemplars. We field large-scale survey experiments to a population sample of journalism students, a nationally representative sample of citizens, and a representative sample of “young people” and obtain evaluations of news value, newsworthiness, and behavioral measures of the actual write-up of news articles. We find significant support for the role of editorial policy and limited support for the role of educational socialization and psychological biases. In a time where economic pressures and the proliferation of digital media potentially lead editors to prioritize clickbait, these findings suggest that structural biases in news coverage may be aggravated.
Interstitial fluid transport in a multi-compartment model of cerebral blood flow
Authors: Payne Stephen
Published: December 2023

Whole brain models are a valuable tool to gain a better understanding of cerebral blood flow and metabolism. Recent work has developed multi-compartment models of blood flow and oxygen transport that can be used in a finite element framework to simulate whole brain behaviour with low computational expense, helping to move such tools towards clinical application. However, the transport of fluid between the vascular space and the interstitial space has not yet been considered in detail in this context, despite this playing an important role in several cerebrovascular diseases. In this study, an extended framework is proposed to include this transport, coupled with a linear elastic model of tissue displacement to simulate the movement of fluid and the resulting displacement of brain tissue. This framework is compared in detail with previous models. The resulting equations are found to exhibit multiple time scales, and a separation of scales is performed to analyse the behaviour at different time scales. Finally, a simplified model is proposed that can be easily implemented within existing computational frameworks, providing a valuable extension of the pathological conditions that can be simulated.
Aberrant accumulation of ceramides in mitochondria triggers cell death by inducing autophagy in Arabidopsis
Authors: Bao He-Nan , Yin Jian , Wang Ling-Yan , Wang Rui-Hua , Huang Li-Qun , Chen Yi-Li , Wu Jian-Xin , Sun Jia-Qi , Liu Wei-Wei , Yao Nan , Li Jian
Published: December 2023

Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.
Identification of promoter targets by Aureochrome 1a in the diatom Phaeodactylum tricornutum
Authors: Im Soo Hyun , Lepetit Bernard , Mosesso Niccolò , Shrestha Sandeep , Weiss Laura , Nymark Marianne , Roellig Robert , Wilhelm Christian , Isono Erika , Kroth Peter G
Published: December 2023

Aureochromes (AUREOs) are unique blue light receptors and transcription factors found only in stramenopile algae. While each of the four AUREOs identified in the diatom Phaeodactylum tricornutum may have a specific function, PtAUREO1a has been shown to have a strong impact on overall gene regulation, when light changes from red to blue light conditions. Despite its significance, the molecular mechanism of PtAUREO1a is largely unexplored. To comprehend the overall process of gene regulation by PtAUREO1a, we conducted a series of in vitro and in vivo experiments, including pull-down assays, yeast one-hybrid experiments, and phenotypical characterization using recombinant PtAUREOs and diatom mutant lines expressing a modified PtAureo1a gene. We describe the distinct light absorption properties of four PtAUREOs and the formation of all combinations of their potential dimers. We demonstrate the capability of PtAUREO1a and 1b to activate the genes, diatom-specific cyclin 2, PtAureo1a, and PtAureo1c under both light and dark conditions. Using mutant lines expressing a modified PtAUREO1a protein with a considerably reduced light absorption, we found novel evidence that PtAUREO1a regulates the expression of PtLHCF15, which is essential for red light acclimation. Based on current knowledge, we present a working model of PtAUREO1a gene regulation properties.
Environmental regulation of male fertility is mediated through Arabidopsis transcription factors bHLH89, 91, and 10
Authors: Robson Jordan K , Tidy Alison C , Thomas Stephen G , Wilson Zoe A
Published: December 2023

Formation of functional pollen and successful fertilization rely on the spatial and temporal regulation of anther and pollen development. This process responds to environmental cues to maintain optimal fertility despite climatic changes. Arabidopsis transcription factors basic helix–loop–helix (bHLH) 10, 89, and 91 were previously thought to be functionally redundant in their control of male reproductive development, however here we show that they play distinct roles in the integration of light signals to maintain pollen development under different environmental conditions. Combinations of the double and triple bHLH10,89,91 mutants were analysed under normal (200 μmol m–2 s–1) and low (50 μmol m–2 s–1) light conditions to determine the impact on fertility. Transcriptomic analysis of a new conditionally sterile bhlh89,91 double mutant shows differential regulation of genes related to sexual reproduction, hormone signal transduction, and lipid storage and metabolism under low light. Here we have shown that bHLH89 and bHLH91 play a role in regulating fertility in response to light, suggesting that they function in mitigating environmental variation to ensure fertility is maintained under environmental stress.
Low sucrose availability reduces basal spikelet fertility by inducing abscisic acid and jasmonic acid synthesis in wheat
Authors: Sun Wan , Lu Chongjing , Wen Liangyun , Liu Yaqun , Zhou Xiaohan , Xiao Xuechen , Guo Xiaolei , Wang Zhimin , Sun Zhencai , Zhang Zhen , Zhang Yinghua
Published: December 2023

Within a spike of wheat, the central spikelets usually generate three to four fertile florets, while the basal spikelets generate zero to one fertile floret. The physiological and transcriptional mechanism behind the difference in fertility between the basal and central spikelets is unclear. This study reports a high temporal resolution investigation of transcriptomes, number and morphology of floret primordia, and physiological traits. The W6.5–W7.5 stage was regarded as the boundary to distinguish between fertile and abortive floret primordia; those floret primordia reaching the W6.5–W7.5 stage during the differentiation phase (3–9 d after terminal spikelet stage) usually developed into fertile florets in the next dimorphism phase (12–27 d after terminal spikelet stage), whereas the others aborted. The central spikelets had a greater number of fertile florets than the basal spikelets, which was associated with more floret primordia reaching the W6.5–W7.5 stage. Physiological and transcriptional results demonstrated that the central spikelets had a higher sucrose content and lower abscisic acid (ABA) and jasmonic acid (JA) accumulation than the basal spikelets due to down-regulation of genes involved in ABA and JA synthesis. Collectively, we propose a model in which ABA and JA accumulation is induced under limiting sucrose availability (basal spikelet) through the up-regulation of genes involved in ABA and JA synthesis; this leads to floret primordia in the basal spikelets failing to reach their fertile potential (W6.5–W7.5 stage) during the differentiation phase and then aborting. This fertility repression model may also regulate spikelet fertility in other cereal crops and potentially provides genetic resources to improve spikelet fertility.
Phosphoregulation in the N-terminus of NRT2.1 affects nitrate uptake by controlling the interaction of NRT2.1 with NAR2.1 and kinase HPCAL1 in Arabidopsis
Authors: Li Zhi , Na Wu Xu , Jacquot Aurore , Chaput Valentin , Adamo Mattia , Neuhäuser Benjamin , Straub Tatsiana , Lejay Laurence , Schulze Waltraud X
Published: December 2023

NRT2.1, the major high affinity nitrate transporter in roots, can be phosphorylated at five different sites within the N- and the C-terminus. Here, we characterized the functional relationship of two N-terminal phosphorylation sites, S21 and S28, in Arabidopsis. Based on a site-specific correlation network, we identified a receptor kinase (HPCAL1, AT5G49770), phosphorylating NRT2.1 at S21 and resulting in active nitrate uptake. HPCAL1 itself was regulated by phosphorylation at S839 and S870 within its kinase domain. In the active state, when S839 was dephosphorylated and S870 was phosphorylated, HPCAL1 was found to interact with the N-terminus of NRT2.1, mainly when S28 was dephosphorylated. Phosphorylation of NRT2.1 at S21 resulted in a reduced interaction of NRT2.1 with its activator NAR2.1, but nitrate transport activity remained. By contrast, phosphorylated NRT2.1 at S28 enhanced the interaction with NAR2.1, but reduced the interaction with HPCAL1. Here we identified HPCAL1 as the kinase affecting this phospho-switch through phosphorylation of NRT2.1 at S21.
Pyramiding of transgenic immune receptors from primary and tertiary wheat gene pools improves powdery mildew resistance in the field
Authors: Koller Teresa , Camenzind Marcela , Jung , Esther , Brunner Susanne , Herren Gerhard , Armbruster Cygni , Keller Beat
Published: December 2023

Introgression of resistance genes from wild or related species is a common strategy to improve disease resistance of wheat cultivars. Pm17 is a gene that confers powdery mildew resistance in wheat. It encodes an NLR type of immune receptor and was introgressed from rye to wheat as part of the 1RS chromosome arm translocation several decades ago. So far it has not been possible to separate Pm17 from its co-introgressed rye genes due to suppressed recombination. Here we tested in the field transgenic Bobwhite wheat overexpressing Pm17 without any other rye genes. Four transgenic events showed high levels of PM17 protein accumulation, strong powdery mildew resistance, and no pleiotropic effects during three field seasons. We used a combined approach of transgene insertion and cross-breeding to generate lines co-expressing Pm17 and Pm3, or Pm17 and Pm8. Blumeria graminis f. sp. tritici infection tests confirmed additive, race-specific resistance of the two pyramided transgenes in lines Pm17+Pm3b and Pm17+Pm8. Furthermore, pyramided lines showed strong powdery mildew resistance during three field seasons. We conclude that the combination of overexpressed NLR genes from the extended gene pool broadens and diversifies wheat disease resistance.
Deep Learning Approach for High-accuracy Electron Counting of Monolithic Active Pixel Sensor-type Direct Electron Detectors at Increased Electron Dose
Authors: Wei Jingrui , Moore Kalani , Bammes Benjamin , Levin Barnaby D A , Hagopian Nicholas , Jacobs Ryan , Morgan Dane , Voyles Paul M
Published: December 2023

Electron counting can be performed algorithmically for monolithic active pixel sensor direct electron detectors to eliminate readout noise and Landau noise arising from the variability in the amount of deposited energy for each electron. Errors in existing counting algorithms include mistakenly counting a multielectron strike as a single electron event, and inaccurately locating the incident position of the electron due to lateral spread of deposited energy and dark noise. Here, we report a supervised deep learning (DL) approach based on Faster region-based convolutional neural network (R-CNN) to recognize single electron events at varying electron doses and voltages. The DL approach shows high accuracy according to the near-ideal modulation transfer function (MTF) and detector quantum efficiency for sparse images. It predicts, on average, 0.47 pixel deviation from the incident positions for 200 kV electrons versus 0.59 pixel using the conventional counting method. The DL approach also shows better robustness against coincidence loss as the electron dose increases, maintaining the MTF at half Nyquist frequency above 0.83 as the electron density increases to 0.06 e−/pixel. Thus, the DL model extends the advantages of counting analysis to higher dose rates than conventional methods.
The Magellanic Puzzle: origin of the periphery
Authors: Massana Pol , Nidever David L , Olsen Knut
Published: December 2023

In this paper, we analyse the metallicity structure of the Magellanic Clouds using parameters derived from the Gaia Data Release 3 (DR3) low-resolution XP (for Blue/Red Photometer) spectra, astrometry, and photometry. We find that the qualitative behaviour of the radial metallicity gradients in the Large Magellanic Cloud (LMC) and Small Magellanic Cloud (SMC) is quite similar, with both of them having a metallicity plateau at intermediate radii and a second at larger radii. The LMC has a first metallicity plateau at [M/H] ≈ −0.8 for 3–7°, while the SMC has one at [M/H] ≈ −1.1 for 3–5°. The outer LMC periphery has a fairly constant metallicity of [M/H] ≈ −1.0 (10–18°), while the outer SMC periphery has a value of [M/H] ≈ −1.3 (6–10°). The sharp drop in metallicity in the LMC at ∼8° and the marked difference in age distributions in these two regions suggest that there were two important evolutionary phases in the LMC. In addition, we find that the Magellanic periphery substructures, likely Magellanic debris, are mostly dominated by LMC material stripped off in old interactions with the SMC. This presents a new picture in contrast with the popular belief that the debris around the clouds had been mostly stripped off from the SMC due to having a lower mass. We perform a detailed analysis for each known substructure and identify its potential origin based on metallicities and motions with respect to each galaxy.
Photometric determination of main-sequence binaries with Gaia
Authors: Wallace A L
Published: December 2023

Since its launch in 2013, the Gaia space telescope has provided precise measurements of the positions and magnitudes of over 1 billion stars. This has enabled extensive searches for stellar and substellar companions through astrometric and radial velocity measurements. However, these surveys require a prior knowledge of any unresolved companion affecting the results which can be identified using photometry. In this work, Gaia’s magnitude measurements are combined with near-infrared observations from the Two Micron All Sky Survey (2MASS) and Wide-field Infrared Survey Explorer (WISE) catalogues and simulation-based inference is applied to constrain astrophysical parameters and search for hidden companions. This method is first tested on simulated sets of binary stars before expanding to Gaia’s non-single star catalogue. Using this test, a region is identified on the H–R diagram in which the method is the most accurate and all Gaia sources within that region are analysed. This analysis reproduces a known anticorrelation between metallicity and binary fraction. Finally, the method is applied to the nearby star cluster M67 and, using previous studies of the metallicity distribution, it is possible to improve constraints on binary fraction. From this the binary fraction in the cluster is calculated to vary from 30 per cent in the outer cluster to 45 per cent near the core. This is found to be significantly higher the 23 per cent binary fraction calculated for the wider stellar neighbourhood.
Population synthesis and parameter estimation of neutron stars with continuous gravitational waves and third-generation detectors
Authors: Hua Yuhan , Wette Karl , Scott Susan M , Pitkin Matthew D
Published: December 2023

Precise measurement of stellar properties through the observation of continuous gravitational waves from spinning non-axisymmetric neutron stars can shed light onto new physics beyond terrestrial laboratories. Although hitherto undetected, prospects for detecting continuous gravitational waves improve with longer observation periods and more sensitive gravitational wave detectors. We study the capability of the Advanced Laser Interferometer Gravitational-Wave Observatory, and the Einstein Telescope to measure the physical properties of neutron stars through continuous gravitational wave observations. We simulate a population of Galactic neutron stars, assume continuous gravitational waves from the stars have been detected, and perform parameter estimation of the detected signals. Using the estimated parameters, we infer the stars’ moments of inertia, ellipticities, and the components of the magnetic dipole moment perpendicular to the rotation axis. The estimation of the braking index proved challenging and is responsible for the majority of the uncertainties in the inferred parameters. Using the Einstein Telescope with an observation period of $5\, {\rm {yr}}$, point estimates using median can be made on the moments of inertia with error of $\sim 10\!-\!100~{{\ \rm per\ cent}}$ and on the ellipticities with error of $\sim 5\!-\!50~{{\ \rm per\ cent}}$, subject to the inference of the braking index. The perpendicular magnetic dipole moment could not be accurately inferred for neutron stars that emit mainly gravitational waves.
New constraints on the molecular gas content of a z ∼ 8 galaxy from JVLA CO(J = 2–1) observations
Authors: Jones Gareth C , Witstok Joris , Concas Alice , Laporte Nicolas
Published: December 2023

As the primary fuel for star formation, molecular gas plays a key role in galaxy evolution. A number of techniques have been used for deriving the mass of molecular reservoirs in the early Universe (e.g. [C ii]158 µm, [C i], dust continuum), but the standard approach of CO-based estimates has been limited to a small number of galaxies due to the intrinsic faintness of the line. We present Jansky Very Large Array observations of the $z\sim \, 8.31$ galaxy MACS0416_Y1, targeting CO(2-1) and rest-frame radio continuum emission, which result in upper limits on both quantities. Adding our continuum limit to the published far-infrared (FIR) spectral energy distribution, we find a small non-thermal contribution to the FIR emission, a low-dust mass (${\rm {\log }}_{10}({\rm {\mathit{ M}}}_{\rm {D}}/{\rm M}_{\odot })\sim 5$), and an abnormally high-dust temperature (${\rm \mathit{ T}}_{\rm D}\gtrsim \, 90\, \mathrm{ K}$) that may indicate a recent starburst. Assuming a low metallicity (Z/Z⊙ ∼ 0.25), we find evidence for $M_{{\rm {H}}_2}, \mathrm{ CO}\lesssim \, 10^{10}$ M⊙, in agreement with previous [C ii] investigations ($M_{{\rm {H}}_2},[\mathrm{ C}\,\small{\rm II}]\, \sim \, 10^{9.6}$ M⊙). Upcoming JWST observations of this source will result in a precise determination of Z, enabling better constraints and an unprecedented view of the gaseous reservoir in this primordial starburst galaxy.
Are patients with primary glomerular disease at increased risk of malignancy?
Authors: Han Jialin , Zhao Yinshan , Canney Mark , Atiquzzaman Mohammad , Keown Paul , Levin Adeera , Barbour Sean
Published: December 2023

Over the past decade, several observational studies and case series have provided evidence suggesting a connection between glomerular diseases and the development of malignancies, with an estimated risk ranging from 5 to 11%. These malignancies include solid organ tumours as well as haematologic malignancies such as lymphoma and leukaemia. However, these risk estimates are subject to several sources of bias, including unmeasured confounding from inadequate exploration of risk factors, inclusion of glomerular disease cases that were potentially secondary to an underlying malignancy, misclassification of glomerular disease type and ascertainment bias arising from an increased likelihood of physician encounters compared with the general population. Consequently, population-based studies that accurately evaluate the cancer risk in glomerular disease populations are lacking. While it is speculated that long-term use of immunosuppressive medications and glomerular disease activity measured by proteinuria and estimated glomerular filtration rate may be associated with cancer risk in patients with glomerular disease, the independent role of these risk factors remains largely unknown. The presence of these knowledge gaps could lead to a lack of awareness of cancer as a potential chronic complication of glomerular disease, underutilization of routine screening practices in clinical care that allow early diagnosis and treatment of malignancies and underrecognition of modifiable risk factors to decrease the risk of de novo malignancies over time. This review summarizes the current evidence on the risk of cancer in patients with glomerular diseases, explores the limitations of prior studies and discusses methodological challenges and potential solutions for obtaining accurate estimates of cancer risk and identifying modifiable risk factors unique to GN populations.