bluuebunny/crossref_metadata_2025 huggingface dataset:
Arabidopsis Fhit-like tumor suppressor resumes early terminated constitutive triple response1-10 mRNA translation
Authors: Zhang Ranran , Zhang Wei , Wang Chenrunshu , Wen Chi-Kuang
Published: April 2024

The Arabidopsis (Arabidopsis thaliana) constitutive triple response1-10 (ctr1-10) mutant produces a reduced level of CTR1 protein and exhibits a weak ctr1 mutant phenotype. Sequence analysis revealed highly active translation of the upstream open reading frame (uORF) at the extended 5′-UTR of the ctr1-10 mRNA, resulting from T-DNA insertion. Enhancer screening for ctr1-10 isolated the fragile histidine triad-1 (fhit-1) mutation. The fhit-1 ctr1-10 mutant phenotypically resembled strong ctr1 mutants and barely produced CTR1, and the fhit-1 mutation reduced the translation efficiency of ctr1-10 but not that of CTR1 mRNA. The human (Homo sapiens) Fhit that involves tumorigenesis and genome instability has the in vitro dinucleotide 5′,5′″-P1, P3-triphosphate hydrolase activity, and expression of the human HsFHIT or the hydrolase-defective HsFHITH96N transgene reversed the fhit-1 ctr1-10 mutant phenotype and restored CTR1 levels. Genetic editing that in situ disrupts individual upstream ATG codons proximal to the ctr1-10 mORF elevated CTR1 levels in ctr1-10 plants independent of FHIT. EUKARYOTIC INITIATION FACTOR3G (eIF3G), which is involved in translation and reinitiation, interacted with FHIT, and both were associated with the polysome. We propose that FHIT resumes early terminated ctr1-10 mORF translation in the face of active and complex uORF translation. Our study unveils a niche that may lead to investigations on the molecular mechanism of Fhit-like proteins in translation reinitiation. The biological significance of FHIT-regulated translation is discussed.
Pharmacodynamic effects following co-administration of cannabinoids and opioids: a scoping review of human experimental studies
Authors: Guy David , Wootten Jared C , Wong Michael , Turski Daniel , Lukewich Mark , Alboog Abdulrahman , Kandasamy Abirami R , Gregory Jonathan , Poolacherla Raju
Published: April 2024

Background

Cannabinoids are increasingly used in the management of chronic pain. Although analgesic potential has been demonstrated, cannabinoids interact with a range of bodily functions that are also influenced by chronic pain medications, including opioids.

Objective

We performed a scoping review of literature on the pharmacodynamic effects following the co-administration of cannabinoids and opioids.

Methods

We systematically searched EMBASE, PubMed, and PsycINFO for studies that experimentally investigated the co-effects of cannabinoids and opioids in human subjects. Available evidence was summarized by clinical population and organ system. A risk of bias assessment was performed.

Results

A total of 16 studies met the inclusion criteria. Study populations included patients with chronic non-cancer and cancer pain on long-term opioid regimens and healthy young adults without prior exposure to opioids who were subject to experimental nociceptive stimuli. Commonly administered cannabinoid agents included Δ9-tetrahydrocannabinol and/or cannabidiol. Co-administration of cannabinoids and opioids did not consistently improve pain outcomes; however, sleep and mood benefits were observed in chronic pain patients. Increased somnolence, memory and attention impairment, dizziness, gait disturbance, and nauseousness and vomiting were noted with co-administration of cannabinoids and opioids. Cardiorespiratory effects following co-administration appeared to vary according to duration of exposure, population type, and prior exposure to cannabinoids and opioids.

Conclusions

The available evidence directly investigating the pharmacodynamic effects following co-administration of cannabinoids and opioids for non-analgesic outcomes is scarce and suffers from a lack of methodological reporting. As such, further research in this area with comprehensive methodologic reporting is warranted.
Impression Management and Expectations of Political Cynicism
Authors: Style Hillary K
Published: April 2024

There are many warnings about growing political cynicism in the news and political science literature. While some people may be truly cynical about politics, for others cynical responses to politics may be a form of impression management—the practice of presenting oneself to others in the way one wishes to be perceived. In three studies, I demonstrate that people report they are cynical in order to avoid giving the impression they do not know much about politics. Political cynicism is not a “socially desirable” characteristic—people do not believe cynicism is normatively good. At the same time, many see value to cynicism in politics, a finding which carries broad implications for the relationship between cynicism and perceived knowledge in political discourse.
Prognosis of Pain After Stroke During Rehabilitation Depends on the Pain Quality
Authors: Uragami Shinji , Osumi Michihiro , Sumitani Masahiko , Fuyuki Masanori , Igawa Yuki , Iki Shinya , Koga Masayuki , Tanaka Yoichi , Sato Gosuke , Morioka Shu
Published: April 2024

Objective

Pain after a stroke interferes with daily life and the rehabilitation process. This study aimed to clarify the prognosis of pain in subgroups of patients with pain after a stroke using pain quality data.

Methods

The study included 85 patients with pain after stroke undergoing exercise-based rehabilitation. Items of the Neuropathic Pain Symptom Inventory (NPSI) were used, and patients with pain after stroke were clustered according to their scores of NPSI. Other clinical assessments, such as physical and psychological conditions, were assessed by interviews and questionnaires, and then these were compared among subgroups in a cross-sectional analysis. Longitudinal pain intensity in each subgroup was recorded during 12 weeks after the stroke and the patients’ pain prognoses were compared between subgroups.

Results

Four distinct subgroups were clustered: cluster 1 (cold-evoked pain and tingling), cluster 2 (tingling only), cluster 3 (pressure-evoked pain), and cluster 4 (deep muscle pain with a squeezing and pressure sensation). The cross-sectional analysis showed varying clinical symptoms among the subgroups, with differences in the prevalence of joint pain, limited range of motion, somatosensory dysfunction, and allodynia. There were no significant differences in pain intensity at baseline among the subgroups. A longitudinal analysis showed divergent prognoses of pain intensity among the subgroups. The pain intensity in cluster 4 was significantly alleviated, which suggested that musculoskeletal pain could be reduced with conventional exercise-based rehabilitation. However, the pain intensity of patients in clusters 1 and 2 remained over 12 weeks.

Conclusion

The study classified patients into clinically meaningful subgroups using pain quality data and provided insight into their prognosis of pain. The findings could be useful for guiding personalized rehabilitation strategies for pain management.

Impact

Assessment of pain quality in patients with pain after stroke leads to personalized rehabilitation for pain management.
Long-term clinical outcomes in early rheumatoid arthritis that was treated-to-target in the BeSt and IMPROVED studies
Authors: Heckert Sascha Louise , Maassen Johanna M , Nevins Isabell , Baudoin Paul , Steup-Beekman Gerda M , Huizinga Tom W J , Bergstra Sytske Anne , Allaart Cornelia F
Published: April 2024

Objectives

To assess disease outcomes after 20 and 12 years of patients with RA or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials.

Methods

In BeSt (inclusion 2000–02, duration 10 years), 508 patients with early RA were randomized to: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial csDMARD combination therapy, 4. initial bDMARD/csDMARD combination therapy. The treatment target was low disease activity (DAS ≤ 2.4).

In IMPROVED (inclusion 2007–10, duration 5 years), 610 patients with early RA/UA started MTX with prednisone bridging. The treatment target was remission (DAS < 1.6). Patients not in early remission were randomized to 1. csDMARD combination therapy or 2. bDMARD/csDMARD combination therapy.

Between 2019 and 22, these patients were invited for long-term follow-up.

Results

One-hundred-fifty-three ex-Best and 282 ex-IMPROVED patients participated in the follow-up study after a median of 12 and 20 years since the study started.

In ex-BeSt and ex-IMPROVED patients, the rate of low disease activity was 91%, and 68% were in DAS remission. Median SHS was 14.0 in ex-BeSt (IQR 6.0–32.5; progression since end BeSt 6.0, IQR 2.0–12.5) and 8 in ex-IMPROVED participants (IQR 3–16; progression since end IMPROVED 4, IQR 2–9). Mean HAQ was 0.8 ± 0.6 in ex-BeSt (change since end BeSt: 0.3 ± 0.5) and 0.6 ± 0.6 in ex-IMPROVED participants (change since end IMPROVED: 0.06 ± 0.5).

Conclusion

At 12/20 years after treatment started, the majority of RA and UA patients who had been treated to target low DAS or DAS remission were in DAS remission and had limited functional disability. Radiographic damage progression was mild although not completely suppressed.
Tackling the environmental cost of digital technology: Some reflections on a soft law instrument on sustainability in contracts
Authors: Feleppa Margherita
Published: April 2024

This article explores the convergence of digital innovation and its negative consequences (such as e-waste) with modern sustainability goals by looking at contracts. Specifically, it discusses the use of sustainability contract clauses (SCCs) in business contracts as an expression of corporate social responsibility and of self-regulation. It suggests that there is potential in promoting the use of sustainable obligations in the electronics supply chain (the generator of the fastest growing waste source). As little guidance exists on sustainable obligations, this article discusses the possibility of establishing a new soft law instrument that could tackle some of the described legal challenges in the current use of SCCs. In doing so, it reflects on the possible issues of the proposed instrument.
Nonclinical Investigation of Cytokine Mitigation Strategies for T-cell–Engaging Bispecifics in the Cynomolgus Macaque
Authors: Kamperschroer Cris , Guffroy Magali , Shen Amy , Dokmanovich Melba , Stubbs Makeida , O’Donnell Lynn M.
Published: April 2024

T-cell–directed cancer therapies such as T-cell–engaging bispecifics (TCBs) are commonly associated with cytokine release syndrome and associated clinical signs that can limit their tolerability and therapeutic benefit. Strategies for reducing cytokine release are therefore needed. Here, we report on studies performed in cynomolgus monkeys to test different approaches for mitigating cytokine release with TCBs. A “priming dose” as well as subcutaneous dosing reduced cytokine release compared with intravenous dosing but did not affect the intended T-cell response to the bispecific. As another strategy, cytokines or cytokine responses were blocked with an anti-IL-6 antibody, dexamethasone, or a JAK1/TYK2-selective inhibitor, and the effects on toxicity as well as T-cell responses to a TCB were evaluated. The JAK1/TYK2 inhibitor and dexamethasone prevented CRS-associated clinical signs on the day of TCB administration, but the anti-IL-6 had little effect. All interventions allowed for functional T-cell responses and expected damage to target-bearing tissues, but the JAK1/TYK2 inhibitor prevented the upregulation of activation markers on T cells, suggesting the potential for suppression of T-cell responses. Our results suggest that short-term prophylactic dexamethasone treatment may be an effective option for blocking cytokine responses without affecting desired T-cell responses to TCBs.
Influence of regression, its extent and tumor-infiltrating lymphocytes on sentinel node status, relapse, and survival in a 10-year retrospective study of melanoma patients
Authors: Maione Vincenzo , Perantoni Martina , Bettolini Luca , Bighetti Stefano , Arisi Mariachiara , Tomasi Cesare , Incardona Paolo , Calzavara-Pinton Piergiacomo
Published: April 2024

This case-control study seeks to investigate the influence of histological findings, specifically regression, its extent and tumor-infiltrating lymphocyte (TILs), on result of sentinel lymph node (SLN) biopsy, 5-year melanoma-specific survival (MSS), and relapse-free survival (RFS). We included all patients with cutaneous melanoma who underwent SLN biopsy at the Melanoma Center of the University of Brescia, following the Italian Association of Medical Oncology National guidelines from January 2008 to August 2018. Regression and its extent (<75 or ≥75%) and the presence of TILs were reevaluated by a trained dermatopathologist, adhering to the 2017 College of American Pathologists Cancer Protocol for Skin Melanoma. These patients were followed up for 5 years. Our study uncovered significant associations between regression and male sex (P < 0.05), melanoma location on the trunk, upper limbs, and back (P = 0.001), ulceration (P < 0.05), lower Breslow thickness (P = 0.001), and the presence of lymphocytic infiltration (both brisk and nonbrisk) (P < 0.001). Regression and its extent, however, did not appear to affect SLN positivity (P = 0.315). Similarly, our data did not reveal a correlation between TILs and result of SLN biopsy (P = 0.256). When analyzing MSS and RFS in relation to the presence or absence of regression and TILs, no statistically significant differences were observed, thus precluding the need for logistic regression and Kaplan–Meier curve analysis. This study’s findings underscore that regression and TILs do not appear to exert an influence on sentinel lymph node status,, MSS, or RFS in our cohort of patients.
Characterizing the “HIV Care Adherence Journey” for Persons With HIV in the Philippines: Conceptual Foundation for Person-Centered Intervention
Authors: De Torres Ryan Q. , Operario Don
Published: April 2024

Promoting adherence to HIV care among persons with HIV (PWH) is a key component to addressing the rising HIV epidemic in the Philippines. HIV care adherence is a complex process that may change throughout an individual's life course or “journey” living with HIV. This qualitative study aimed to explore the HIV care adherence journey of PWH. Maximum variation sampling was used to select 12 PWH and 3 health care providers for in-depth online interviews, which were analyzed using thematic analysis. The four themes that emerged to describe the HIV care adherence journey are integration, relation, navigation, and manifestation. Each theme corresponds to a unique set of activities and goals related to PWH's lived experiences as they initiate, practice, and maintain care adherence. This study provides a preliminary framework to characterize the HIV care adherence journey as a dynamic, complex, and multifaceted phenomenon, which can help to inform holistic interventions to support PWH.
Association between neutrophil-to-lymphocyte ratio and outcomes in hospitalized patients with left ventricular thrombus
Authors: Che Yingxia , Huang Shenglan , Zhou Wei , Shi Shunyi , Ye Fei , Ji Yuan , Huang Jun
Published: April 2024

Background

Left ventricular thrombus (LVT) is a severe cardiovascular complication occurring in approximately 10% of patients with acute anterior ST-segment elevation myocardial infarction. This study aimed to evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) in patients with LVT.

Material and methods

This multicenter retrospective study was conducted between January 2000 and June 2022 in hospitalized patients with LVT. The outcome included in-hospital MACCE. The association between NLR and in-hospital MACCE was measured by odds ratios (ORs). The restricted cubic spline model was used for dose-response analysis.

Results

A total of 197 LVT patients from four centers were included for analysis in this study. MACCE occurred in 13.7% (27/197) of the patients. After adjusting for estimated glomerular filtration rate (eGFR), D-dimer, and age, the OR for MACCE comparing first to the third tertile of NLR was 13.93 [95% confidence interval: 2.37–81.77, P = 0.004, P-trend = 0.008]. When further adjusting for etiology and heart failure with reduced ejection fraction (HFrEF), the association remained statistically significant. Spline regression models showed an increasing trend in the incidence of MACCEs with NLR both in crude and adjusted models. Subgroup analyses showed that a high NLR may be correlated with poorer outcomes for LVT patients older than 65 years, or with hypertension, dyslipidemia, low ejection fraction, liver, and renal dysfunctions.

Conclusion

In conclusion, these findings suggested that higher NLR may be associated with an increased risk of in-hospital MACCE in patients with LVT.
Taking Control
Authors: Bradley Carol
Published: April 2024

With the explosion in contract labor use and expenses that occurred during the pandemic, health systems are being challenged to better understand, manage, and control how temporary labor is utilized for meeting staffing needs. New contracting strategies and a refocused relationship with third-party agencies can improve the efficient use of contract labor.
Creating a Vibrant Organization Using the Dynamic Leadership Model and a Teaming Approach
Authors: Steinbinder Amy , Sisneros Dorothy
Published: April 2024

The pandemic exposed existing weaknesses in the health care system, and innovative leaders stepped up to address the compounding effects the novel anomaly created. Postpandemic disruption persists, and the behaviors and actions of these positive deviants demonstrate that new ways of leadership are available to those who are willing to embrace the dynamic leadership model and teaming methodology to shape health care delivery of the future. As we look to new ways of being and leading, we begin from a changed world—one that has been reset and cannot go back. Dynamic leaders are called upon to create cultures that reflect the needs of the future workplace and workforce. They pave new pathways and new ways of thinking, reimagine new realities, and create abundance. Their consistent practice of 5 essential behaviors—self-awareness, deep listening, curiosity, empathy, and decisiveness—strengthen their leadership and ability to meet the demands of health care today.
Nurse Leader Mindfulness Pilot Impact on Perceived Stress
Authors: Buckley Christine McNulty , Sipe Margie Hamilton
Published: April 2024

The recent COVID-19 pandemic exacerbated pre-existing stressful conditions in health care, further elevating the risk of negative health outcomes for nurses and particularly nurse leaders. The aim of this pilot project was to assess the efficacy of mindfulness practices in attenuating nurse leaders’ perceived stress levels. There is a lack of evidence regarding the outcomes of stress reduction programs aimed at health care staff, especially for nurse leaders within the clinical setting. Mindfulness has been shown to have a significant positive effect on attenuating stress in a wide variety of populations. This study used a prospective longitudinal design with a volunteer nurse leader group comparing self-reported perceived stress levels before and after a brief mindfulness intervention. Results indicated a significant reduction in perceived stress among volunteer nurse leader participants postintervention. Further investigation is needed in a variety of settings to more fully understand and evaluate the potential impact of introducing mindfulness practices to support nurse leaders in hospital or clinical settings.
Workplace Violence in the Pediatric Emergency Department
Authors: Huang Craig James , Boulos Andrew Kamal , Field Steven , Wang Vincent J. , Yen Kenneth
Published: April 2024

Objectives

Previous work shows that health care workers, and particularly emergency department (ED) staff, are at an above average risk of workplace violence (WPV), defined as verbal threats or physical violence in the workplace. Previous data suggest that staff of a single pediatric ED frequently feel unsafe. The objective of this study was to conduct the first national survey study to assess the prevalence and incidence of WPV in the pediatric ED.

Methods

In this cross-sectional survey study, a representative sample of US pediatric emergency medicine physicians were invited to participate in a national survey adapted from the previously validated Workplace Violence in the Health Sector questionnaire from the World Health Organization. The primary outcome measure was the proportion of physicians who have been exposed to WPV. Rates of exposure to violence, reporting habits, and physician perception of various violence prevention strategies were studied secondarily.

Results

Surveys were completed by 207 (45%) invited participants, representing 31 US children's hospitals. The prevalence of WPV exposure was 96%. Physical violence with a weapon was witnessed by 20% of participants. Injuries requiring medical attention or time off work were experienced by 10% of participants. Half of participants never reported violent events. Security guards were welcome by 99%, armed law enforcement officers by 70%, and metal detectors by 81% of physicians. Self-arming was opposed by 85% of respondents.

Conclusions

Exposure to WPV is frequent among pediatric emergency medicine physicians with a prevalence similar to that of general emergency departments. Workplace violence remains underreported. This national survey contributes to the objective evaluation of individual- and systems-level violence prevention interventions.
Gynecomastia Surgery Patient Education
Authors: Paidisetty Praneet S. , Wang Leonard K. , Shin Ashley , Urbina Jacob , Mitchell David , Quan Amy , Obinero Chioma G. , Chen Wendy
Published: April 2024

Background

YouTube is a platform for many topics, including plastic surgery. Previous studies have shown poor educational value in YouTube videos of plastic surgery procedures. The purpose of this study was to evaluate the quality and accuracy of YouTube videos concerning gynecomastia surgery (GS).

Methods

The phrases “gynecomastia surgery” (GS) and “man boobs surgery” (MB) were queried on YouTube. The first 50 videos for each search term were examined. The videos were rated using our novel Gynecomastia Surgery Specific Score to measure gynecomastia-specific information, the Patient Education Materials Assessment Tool (PEMAT) to measure understandability and actionability, and the Global Quality Scale to measure general quality.

Results

The most common upload source was a board-certified plastic surgeon (35%), and content category was surgery techniques and consultations (51%). Average scores for the Global Quality Scale (x̄ = 2.25), Gynecomastia Surgery Specific Score (x̄ = 3.50), and PEMAT Actionability (x̄ = 44.8%) were low, whereas PEMAT Understandability (x̄ = 77.4%) was moderate to high. There was no difference in all scoring modalities between the GS and MB groups. Internationally uploaded MB videos tended to originate from Asian countries, whereas GS videos tended to originate from non-US Western countries. Patient uploaders had higher PEMAT Actionability scores than plastic surgeon uploaders.

Conclusions

The quality and amount of gynecomastia-specific information in GS videos on YouTube are low and contain few practical, take-home points for patients. However, understandability is adequate. Plastic surgeons and professional societies should strive to create high-quality medical media on platforms such as YouTube.
A Comparative Study of Large Language Models, Human Experts, and Expert-Edited Large Language Models to Neuro-Ophthalmology Questions
Authors: Tailor Prashant D. , Dalvin Lauren A. , Starr Matthew R. , Tajfirouz Deena A. , Chodnicki Kevin D. , Brodsky Michael C. , Mansukhani Sasha A. , Moss Heather E. , Lai Kevin E. , Ko Melissa W. , Mackay Devin D. , Di Nome Marie A. , Dumitrascu Oana M. , Pless Misha L. , Eggenberger Eric R. , Chen John J.
Published: April 2024

Background:

While large language models (LLMs) are increasingly used in medicine, their effectiveness compared with human experts remains unclear. This study evaluates the quality and empathy of Expert + AI, human experts, and LLM responses in neuro-ophthalmology.

Methods:

This randomized, masked, multicenter cross-sectional study was conducted from June to July 2023. We randomly assigned 21 neuro-ophthalmology questions to 13 experts. Each expert provided an answer and then edited a ChatGPT-4–generated response, timing both tasks. In addition, 5 LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, Bard) generated responses. Anonymized and randomized responses from Expert + AI, human experts, and LLMs were evaluated by the remaining 12 experts. The main outcome was the mean score for quality and empathy, rated on a 1–5 scale.

Results:

Significant differences existed between response types for both quality and empathy (P < 0.0001, P < 0.0001). For quality, Expert + AI (4.16 ± 0.81) performed the best, followed by GPT-4 (4.04 ± 0.92), GPT-3.5 (3.99 ± 0.87), Claude (3.6 ± 1.09), Expert (3.56 ± 1.01), Bard (3.5 ± 1.15), and Bing (3.04 ± 1.12). For empathy, Expert + AI (3.63 ± 0.87) had the highest score, followed by GPT-4 (3.6 ± 0.88), Bard (3.54 ± 0.89), GPT-3.5 (3.5 ± 0.83), Bing (3.27 ± 1.03), Expert (3.26 ± 1.08), and Claude (3.11 ± 0.78). For quality (P < 0.0001) and empathy (P = 0.002), Expert + AI performed better than Expert. Time taken for expert-created and expert-edited LLM responses was similar (P = 0.75).

Conclusions:

Expert-edited LLM responses had the highest expert-determined ratings of quality and empathy warranting further exploration of their potential benefits in clinical settings.
The angiogenic growth of cities
Authors: Capel-Timms Isabella , Levinson David , Lahoorpoor Bahman , Bonetti Sara , Manoli Gabriele
Published: April 2024

Describing the space–time evolution of urban population is a fundamental challenge in the science of cities, yet a complete theoretical treatment of the underlying dynamics is still missing. Here, we first reconstruct the evolution of London (UK) over 180 years and show that urban growth consists of an initial phase of diffusion-limited growth, followed by the development of the railway transport network and a consequential shift from central to suburban living. Such dynamics—which are analogous to angiogenesis in biological systems—can be described by a minimalist reaction–diffusion model coupled with economic constraints and an adaptive transport network. We then test the generality of our approach by reproducing the evolution of Sydney, Australia, from 1851 to 2011. We show that the rail system coevolves with urban population, displaying hierarchical characteristics that remain constant over time unless large-scale interventions are put in place to alter the modes of transport. These results demonstrate that transport schemes are first-order controls of long-term urbanization patterns and efforts aimed at creating more sustainable and healthier cities require careful consideration of population–transport feedbacks.
Publishing negative results is good for science
Authors: Bik Elisabeth M.
Published: April 2024

Scientists face challenges in publishing negative results, because most scientific journals are biassed in accepting positive and novel findings. Despite their importance, negative results often go unpublished, leading to duplication of efforts, biassed meta-analyses, and ethical concerns regarding animal and human studies. In this light, the initiative by Access Microbiology to collect and publish negative results in the field of microbiology is a very important and valuable contribution towards unbiassed science.
Loop modelling provides insights into regulation of mTORC1 activity via DEPTOR dimerisation
Authors: Teh Aik-Hong , Hisano Tamao
Published: April 2024

mTOR regulates cell growth by forming the mTORC1 and mTORC2 complexes. DEPTOR partially inhibits mTORC1, which in turn phosphorylates and inactivates it. Despite the mTORC1–DEPTOR structures, the exact mechanism remains unclear largely because functionally flexible key elements, DEPTOR’s linker in particular, are unresolved. By taking DEPTOR’s dimerisation into consideration, our modelling of these missing loops suggests that monomeric DEPTOR bound to mTORC1 in a non-inhibitory mode, while the domain-swapped dimeric DEPTOR could interact with mTORC1’s FRB domain and block the kinase’s catalytic site with its linker. These two states indicate that linker phosphorylation inactivates DEPTOR possibly by disrupting its dimerisation, which could tether the linker to the kinase domain to enhance mTORC1 inhibition. In addition to DEPTOR, mTOR’s kα9b–kα10 loop, which harbours the S2481 autophosphorylation site, and mSIN1’s flexible domains in mTORC2 might act as inhibitory elements too.
Do invasive tetrapods conserve their climatic niches?
Authors: Mahapatra Biswa Bhusana , G Ravikanth , N.A. Aravind
Published: April 2024

Invasive species are the second biggest threat to biodiversity after habitat fragmentation. The species list was collated from the Global Invasive Species Database (GISD) and the Centre for Agricultural and Bioscience International (CABI), and the species occurrence data were downloaded from the Global Biodiversity Information Facility (GBIF). This study examines the niche dynamics of 152 invasive tetrapods and finds that 60% of the species have very low or low niche overlap across the native and introduced regions. There are species with very high niche overlap, such as the Cane toad, Brahminy blind snake, Eurasian collared dove, Whitehead marmoset and Asian house shrew. Around 30% (=46) of species are showing considerable niche expansion. Similarly, 21 species (5 amphibians, 6 reptiles, 6 birds and 4 mammals) show no expansion in the introduced region. The introduction pattern presents that 46 invasive tetrapods are native to Asia, whereas 43 of them are introduced to North America.
Exploring the influence of atmospheric CO2and O2levels on the utility of nitrogen isotopes as proxy for biological N2fixation
Authors: Wannicke Nicola , Stüeken Eva E , Bauersachs Thorsten , Gehringer Michelle M
Published: April 2024

Biological N2fixation (BNF) can be traced to the Archean, over 3 Bya. The nitrogen isotopic fractionation composition (δ15N) of sedimentary rocks is commonly used to reconstruct the presence of diazotrophic ecosystems in the past. While δ15N has been calibrated under modern environmental conditions; it has not under Archean conditions, when atmospheric pO2was lower and pCO2was higher than today. Here we explore δ15N signatures in the laboratory under three simulated atmospheres with (i) elevated CO2and no O2, (ii) present day CO2and O2and (iii) elevated CO2and present day O2, in marine and freshwater, heterocytous cyanobacteria. Additionally, we augment our data set with literature data to examine for more generalized dependencies of δ15N during BNF across the Archaea and Bacteria, including cyanobacteria, and habitats. We find a mean ϵ-value of -1.38 ± 0.95, for all bacteria, including cyanobacteria, across all tested conditions. The expanded data set reveal correlations of isotopic fractionation of BNF with CO2concentrations, toxin production and light, although within 1 ‰. Moreover, correlation showed significant dependency of the magnitude of ϵ to species type, C/N ratios and toxin production in heterocytous cyanobacteria, albeit it within a small range (-1.44 ± 0.89). We therefore conclude that δ15N is likely robust when applied to the Archean, stressing the strong cyanobacterial bias. Interestingly, the increased fractionation (lower ϵ) observed in the toxin producing Nodularia and Nostoc spp. suggests a heretofore unknown role of toxins in modulating nitrogen isotopic signals that warrants further investigation.
3D Imaging Reveals Changes in the Neurovascular Architecture of the Murine Calvarium with Aging
Authors: Horenberg Allison L. , Ren Yunke , Rindone Alexandra N. , Pathak Arvind P. , Grayson Warren L.
Published: April 2024

Calvarial nerves, along with vasculature, influence skull formation during development and following injury, but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging. Studying the spatial distribution of nerves in the skull remains challenging due to a lack of methods to image and quantify 3D structures in intact bone. To visualize calvarial 3D neurovascular architecture, we imaged nerves and endothelial cells with lightsheet microscopy. We employed machine-learning-based segmentation to facilitate high-resolution characterization from post-natal day 0 (P0) to Week 80 (80wk). We found that TUBB3+ nerve density decreased with aging with the frontal bone demonstrating earlier onset age-related nerve loss than the parietal bone. In addition, nerves in the periosteum and dura mater exhibited similar yet distinct temporal patterns of nerve growth and loss. While no difference was observed in TUBB3+ nerves during skeletal maturation (P0 ⟶ 12wk), we did observe an increase in the volume of unmyelinated nerves in the dura mater. Regarding calvarial vasculature, larger CD31hiEmcn-vessel density increased with aging, while CD31hiEmcnhivessel density was reduced. For all nerve markers studied, calvarial nerves maintained a preferential spatial association with CD31hiEmcnhivessels that decreased with aging. Additionally, we used a model of Apert syndrome that demonstrates early coronal suture fusion to explore the impact of suture-related disease on neurovascular architecture. We identified a mild dysregulation of dural nerves and minor shifts in vessel populations. Collectively, this 3D, spatiotemporal characterization of calvarial nerves throughout the lifespan and provides new insights into age-induced neurovascular architecture.
Combining lineage correlations and a small molecule inhibitor to detect circadian control of the cell cycle
Authors: Nikhat Anjoom , Chakrabarti Shaon
Published: April 2024

Chronotherapy has emerged as an exciting possibility for improving treatment regimens in cancer. A strong influence of the circadian clock on the cell cycle is a crucial requirement for successful chronotherapy. However, though a number of molecular interactions have been discovered between these two oscillators, it remains unclear whether these interactions are sufficient to generate emergent control of cellular proliferation. In this work, we computationally explore a strategy to detect clock control over the cell cycle, by computing lineage correlations in cell cycle times in the presence and absence of the clock inhibitor KL001. Using phenomenological models, we and others have previously suggested that the ‘cousin-mother inequality’ – a phenomenon where cousin cells show stronger cell cycle time correlations than mother-daughter pairs, could be leveraged to probe circadian effects on cellular proliferation. Using stochastic simulations calibrated to match HCT116 colon cancer proliferation datasets, we demonstrate that the established gene-networks giving rise to the cell cycle and circadian oscillations are sufficient to generate the cousin-mother inequality. In the presence of KL001 which stabilizes CRY1, our models predict greater than 50% decrease in the cousin-mother inequality, but counter-intuitively, very little change in population growth rates. Our results predict a range of underlying cell cycle times where the cousin-mother inequality should be observed, and consequently suggest the exciting possibility of combining measurements of lineage correlations with KL001 as a probe of circadian clock – cell cycle interactions.
Graft incompatibility between pepper and tomato can be attributed to genetic incompatibility between diverged immune systems
Authors: Thomas Hannah Rae , Gevorgyan Alice , Hermanson Alexandra , Yanders Samantha , Erndwein Lindsay , Norman-Ariztía Matthew , Sparks Erin E. , Frank Margaret H
Published: April 2024

Graft compatibility is the capacity of two plants to form cohesive vascular connections. Tomato and pepper are incompatible graft partners; however, the underlying cause of graft rejection between these two species remains unknown.

We diagnosed graft incompatibility between tomato and diverse pepper varieties based on weakened biophysical stability, decreased growth, and persistent cell death using trypan blue and TUNEL assays. Transcriptomic analysis of cell death in the junction was performed using RNA-sequencing, and molecular signatures for incompatible graft response were characterized based on meta-transcriptomic comparisons with other biotic processes.

We show that tomato is broadly incompatible with diverse pepper cultivars. These incompatible graft partners activate prolonged transcriptional changes that are highly enriched for defense processes. Amongst these processes was broad NLR upregulation and hypersensitive response. Using transcriptomic datasets for a variety of biotic stress treatments, we identified a significant overlap in the genetic profile of incompatible grafting and plant parasitism. In addition, we found over 1000 genes that are uniquely upregulated in incompatible grafts.

Based on NLR overactivity, DNA damage, and prolonged cell death we have determined that tomato and pepper graft incompatibility is likely caused by a form of genetic incompatibility, which triggers a hyperimmune-response.
Directed Evolution of Acoustic Reporter Genes Using High-Throughput Acoustic Screening
Authors: Hurt Robert C. , Jin Zhiyang , Soufi Mohamed , Wong Katie K. , Sawyer Daniel P. , Shen Hao K. , Dutka Przemysław , Deshpande Ramya , Zhang Ruby , Mittelstein David R. , Shapiro Mikhail G.
Published: April 2024

A major challenge in the fields of biological imaging and synthetic biology is noninvasively visualizing the functions of natural and engineered cells inside opaque samples such as living animals. One promising technology that addresses this limitation is ultrasound (US), with its penetration depth of several cm and spatial resolution on the order of 100 µm.1Within the past decade, reporter genes for US have been introduced2,3and engineered4,5to link cellular functions to US signals via heterologous expression in commensal bacteria and mammalian cells. These acoustic reporter genes (ARGs) represent a novel class of genetically encoded US contrast agent, and are based on air-filled protein nanostructures called gas vesicles (GVs).6Just as the discovery of fluorescent proteins was followed by the improvement and diversification of their optical properties through directed evolution, here we describe the evolution of GVs as acoustic reporters. To accomplish this task, we establish high-throughput, semi-automated acoustic screening of ARGs in bacterial cultures and use it to screen mutant libraries for variants with increased nonlinear US scattering. Starting with scanning site saturation libraries for two homologs of the primary GV structural protein, GvpA/B, two rounds of evolution resulted in GV variants with 5- and 14-fold stronger acoustic signals than the parent proteins. We anticipate that this and similar approaches will help high-throughput protein engineering play as large a role in the development of acoustic biomolecules as it has for their fluorescent counterparts.
A major effect locus involved in migration timing is shared by pink and sockeye salmon
Authors: Barry Patrick D. , Tallmon David A. , Howe Natasha S. , Baetscher Diana S. , D’Amelio Katie L. , Vulstek Scott C. , Russell Josh R. , Gharrett Anthony J. , Larson Wesley A.
Published: April 2024

Migration is an important component of the life cycles of many organisms and differences in migration timing can greatly influence fitness. Variation in migration timing (hereafter referred to as run timing) is found in many salmon species and contributes to the portfolio of life history diversity that is vital for maintaining healthy populations. Pink salmon (Oncorhynchus gorbuscha) are composed of temporally isolated lineages that spawn in even and odd years. Here, we focus on early and late runs of pink salmon in Auke Creek, Alaska, which spawn a few weeks apart in the same ≈50m stretch of stream. We conducted low coverage, whole genome sequencing on pink salmon from the early and late runs of both even and odd lineages to investigate the genetic basis of run timing in this system. Within the even lineage we detected a major effect locus displaying high genetic divergence between early and late run individuals on chromosome 10 of the pink salmon genome. This same locus showed a lower - but still elevated - amount of genetic divergence in the odd lineage. The region of high divergence includes the Leucine Rich Repeat Containing 9 gene (lrrc9), and genetic divergence was substantially reduced outside of this gene. Thelrrc9gene also shows high divergence between two ecotypes of sockeye salmon (Oncorhynchus nerka) that differ in both run timing and spawning habitat. Comparison of thelrrc9gene region in pink and sockeye salmon shows that variation within this gene is associated with run timing in both species. However, the polymorphic sites (i.e, SNPs) and run timing alleles are unique to each species and arose from independent mutations following divergence from a common ancestor. These results demonstrate that adaptation in pink salmon can occur at small temporal scales and that complex traits can be controlled by similar genetic mechanisms in multiple species.
Novel 4,400-year-old ancestral component in a tribe speaking a Dravidian language
Authors: Sequeira Jaison Jeevan , Krishna Swathy , van Driem George , Mustak Mohammed Shafiul , Das Ranajit
Published: April 2024

Research has shown that the present-day population on the Indian subcontinent derives its ancestry from at least three components identified with pre-Indo-Iranian agriculturalists once inhabiting the Iranian plateau, pastoralists originating from the Pontic-Caspian steppe and ancient hunter-gatherer related to the Andamanese Islanders. The present-day Indian gene pool represents a gradient of mixtures from these three sources. However, with more sequences of ancient and modern genomes and fine structure analyses, we can expect a more complex picture of ancestry to emerge. In this study, we focus on Dravidian linguistic groups to propose a fourth putative source which may have branched out from the basal Middle Eastern component that gave rise to the Iranian plateau farmer related ancestry. The Elamo-Dravidian theory and the linguistic phylogeny of the Dravidian family tree provide chronological fits for the genetic findings presented here. Our findings show a correlation between the linguistic and genetic lineages in language communities speaking Dravidian languages when they are modelled together. We suggest that this source, which we shall call ‘Proto-Dravidian’ ancestry, emerged around the dawn of the Indus Valley civilisation. This ancestry is distinct from all other sources described so far, and its plausible origin not later than 4,400 years ago on the region between the Iranian plateau and the Indus valley supports a Dravidian heartland before the arrival of Indo-European languages on the Indian subcontinent. Admixture analysis shows that this Proto-Dravidian ancestry is still carried by most modern inhabitants of the Indian subcontinent other than the tribal populations. This momentous finding underscores the importance of population-specific fine structure studies. We also recommend informed sampling strategies for biobanks and to avoid oversimplification of ancestral reconstruction. Achieving this requires interdisciplinary collaboration.
Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning
Authors: Mou Xiang , Ji Daoyun
Published: April 2024

Abstract

Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are activated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and coordinate hippocampal replay to guide subsequent spatial navigation.
Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling
Authors: DeVito Nicholas C. , Nguyen Y-Van , Sturdivant Michael , Plebanek Michael P. , Howell Kaylee , Yarla Nagendra , Jain Vaibhav , Aksu Michael , Beasley Georgia , Theivanthiran Balamayooran , Hanks Brent A.
Published: April 2024

Therapeutic resistance to immune checkpoint blockade has been commonly linked to the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated immune evasion promises to lead to more effective combination therapeutic regimens. Herein, we identify the Hedgehog transcription factor, Gli2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. Mechanistic studies reveal that Gli2 generates an immunotolerant tumor microenvironment through the upregulation of Wnt ligand production and increased prostaglandin synthesis. This pathway drives the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) while also impairing type I conventional dendritic cell, CD8+T cell, and NK cell functionality. Pharmacologic EP2/EP4 prostaglandin receptor inhibition and Wnt ligand inhibition each reverses a subset of these effects, while preventing primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional Gli2 signature correlates with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients, providing a translational roadmap to direct combination immunotherapeutics in the clinic.

SIGNIFICANCE

Gli2-induced EMT promotes immune evasion and immunotherapeutic resistance via coordinated prostaglandin and Wnt signaling.