bluuebunny/crossref_metadata_2025 huggingface dataset:
Tobacco Susceptibility and Use Among Rural Adolescents: The Role of Tobacco Marketing Exposure and Screen Media Use
Authors: Kim Sunny Jung , Fugate-Laus Kendall , Barsell Jeremy , Do Elizabeth K , Hayes Rashelle B , Fuemmeler Bernard F
Published: December 2024

Introduction

Tobacco marketing has been found to increase pro-tobacco attitudes and susceptibilities; yet its impact on rural adolescents lacks research. We aim to examine the association between tobacco marketing exposure, screen use, and susceptibility and use of tobacco among a rural youth sample.

Aims and Methods

Youth (N = 697) enrolled in grades 9–11 that resided in rural counties in Virginia were recruited to participate in a survey in September 2022. We assessed demographics, tobacco use, susceptibility to tobacco use, screen media use, and exposure to tobacco marketing and warning messages.

Results

One in five (n = 144, 20.66%) participants reported using any tobacco products and 394 (56.53%) indicated susceptibility. High engagement in social media and texting were more likely to be tobacco ever users than those who had low engagement with those screen media, X2(1) = 12.00 and X2(1) = 19.40, respectively (ps < .001). Greater exposure to pro-tobacco marketing on social media (odds ratio [OR]: 2.03, 95% CI [1.37 to 3.03]) and higher-grade level (OR: 1.77, 95% CI [1.29 to 2.43]) were significantly associated with a greater likelihood of reporting “ever-use” of tobacco products, while controlling for mother’s education, gender, and ethnicity. Among adolescents who never used tobacco products, a higher grade level was associated with greater susceptibility to initiating tobacco product use (OR: 1.40, 95% CI [1.05 to 1.86]).

Conclusions

In this rural sample, greater social media/text use and exposure to pro-tobacco marketing on social media were significantly associated with tobacco ever use. Identification of these risk factors can help inform potential targets and timing for future tobacco prevention campaigns for rural youth.

Implications

Screen media use, tobacco marketing/warning exposure, and their associations with tobacco use and susceptibility were examined in a study with 697 rural Virginia youth. Heavy social media/text users were more likely to have used tobacco products. Exposure to tobacco marketing on social media and higher grade levels were associated with ever using tobacco. Higher grade levels were linked to increased susceptibility to tobacco use among nonusers. These results highlight the importance of resilience to pro-tobacco marketing on social media, and self-regulation of social media/text use in interventions for tobacco ever users. Early interventions may benefit rural youth who never used tobacco.
Timing of Infection as a Key Driver of Racial/Ethnic Disparities in Coronavirus Disease 2019 Mortality Rates During the Prevaccine Period
Authors: Naraharisetti Ramya , Trangucci Rob , Sakrejda Krzysztof , Masters Nina B , Malosh Ryan , Martin Emily T , Eisenberg Marisa , Link Bruce , Eisenberg Joseph N S , Zelner Jon
Published: December 2024

Disparities in coronavirus disease 2019 mortality are driven by inequalities in group-specific incidence rates (IRs), case fatality rates (CFRs), and their interaction. For emerging infections, such as severe acute respiratory syndrome coronavirus 2, group-specific IRs and CFRs change on different time scales, and inequities in these measures may reflect different social and medical mechanisms. To be useful tools for public health surveillance and policy, analyses of changing mortality rate disparities must independently address changes in IRs and CFRs. However, this is rarely done. In this analysis, we examine the separate contributions of disparities in the timing of infection—reflecting differential infection risk factors such as residential segregation, housing, and participation in essential work—and declining CFRs over time on mortality disparities by race/ethnicity in the US state of Michigan. We used detailed case data to decompose race/ethnicity-specific mortality rates into their age-specific IR and CFR components during each of 3 periods from March to December 2020. We used these estimates in a counterfactual simulation model to estimate that that 35% (95% credible interval, 30%–40%) of deaths in black Michigan residents could have been prevented if these residents were infected along the timeline experienced by white residents, resulting in a 67% (61%–72%) reduction in the mortality rate gap between black and white Michigan residents during 2020. These results clearly illustrate why differential power to “wait out” infection during an infectious disease emergency—a function of structural racism—is a key, underappreciated, driver of inequality in disease and death from emerging infections.
The Caregiver Pathway Intervention Can Contribute to Reduced Post-Intensive Care Syndrome Among Family Caregivers of ICU Survivors: A Randomized Controlled Trial
Authors: Watland Solbjørg , Solberg Nes Lise , Ekeberg Øivind , Rostrup Morten , Hanson Elizabeth , Ekstedt Mirjam , Stenberg Una , Hagen Milada , Børøsund Elin
Published: December 2024

Objectives:

Explore short-term effects of “The Caregiver Pathway,” an intervention for family caregiver follow-up, on Post-Intensive Care Syndrome symptoms among families (PICS-F).

Design:

A randomized controlled trial.

Setting:

A medical ICU at a Norwegian University Hospital.

Participants:

One hundred ninety-six family caregivers of critically ill patients randomized to an intervention (n = 101) or control group (n = 95).

Interventions:

“The Caregiver Pathway” four-step model offers individual and structured follow-up, including: 1) mapping family caregivers’ needs and concerns with an assessment tool followed by a conversation with an ICU nurse within the first days at the ICU, 2) a supportive card when leaving the ICU, 3) offer for the family caregivers to receive a phone call after ICU patient discharge, and 4) a follow-up conversation within 3 months.

Measurements and Main Results:

Data were collected at baseline and after 3 months and analyzed using linear regression. No significant effects were detected when comparing all participants completing 3-month outcome measurements (n = 144). A subgroups analysis stratified on patient survival, however, showed statistically significant effect for family caregivers of patients surviving the ICU stay receiving the intervention compared with controls. Caregivers of surviving patients reported improved symptoms related to post-traumatic stress disorder, measured by Impact of Event Scale-Revised (B = –8.2 [95% CI, –14.2 to –2.2]; p = 0.008), anxiety (B = –2.2 [95% CI, –4.0 to –0.5]; p = 0.014), and depression (B = –1.5 [95% CI, –2.9 to –0.1]; p = 0.035); measured by the Hospital Anxiety and Depression Scale, subscore physical functioning in health-related quality of life (B = 9.7 [95% CI, 0.3–19.0]; p = 0.043); measured by Short Form 12-Item Health Survey; and hope (B = 2.4 [95% CI, 0.4–4.3]; p = 0.017) and measured by the Herth Hope Index. At 3-month, the model did not appear to improve the outcomes for family caregivers of nonsurviving patients.

Conclusions:

“The Caregiver Pathway” intervention was associated with reduced symptoms of PICS-F in family caregivers of surviving ICU patients compared with controls.
Dietary polyunsaturated fatty acids and gastric cancer
Authors: Le Ngoan Tran , Pham Yen Thi-Hai , Le Linh Thuy , Ha Ta Nguyen , Le Chung Thi-Kim , Guo Xingyi , Cullen Jennifer , Luu Hung N.
Published: December 2024

Polyunsaturated fatty acids (PUFAs) are fatty acids, containing more than one double bond and have both anti-inflammatory properties and inhibit tumor progression effects as well as carcinogenic properties. There is inconclusive evidence regarding the effect of PUFA intake on gastric cancer in diverse populations. We, therefore, aimed to determine the association between PUFA intake and risk of gastric cancer in a hospital-based case-control study comprising 1182 incident cases of gastric cancer and 2965 controls in Vietnam. A semiquantitative validated food frequency questionnaire was used to derive PUFA intake. Unconditional logistic regression model was applied to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer in relation to PUFA intake. Overall, there was a dose–response inverse association between PUFA intake and gastric cancer risk (ORper-SD increment = 0.72, 95% CI: 0.65–0.79; P
trend < 0.001). Compared with quintile 1 (the lowest quintile), the ORs and respective 95% CIs of gastric cancer for quintiles 2, 3, 4, and 5 of the PUFA intake were 0.65 (0.52–0.80), 0.51 (0.41–0.64), 0.47 (0.37–0.59), and 0.37 (0.28–0.48), respectively. A similar pattern was observed in both sexes and individuals aged <60 years and those aged 60 years or older. In summary, we found a risk reduction of gastric cancer in individuals with a higher intake of PUFA in the Vietnamese population, regardless of sex or age. Our findings have great implications for the prevention and control programs against gastric cancer in low-middle-income countries and similar limited-resource settings.
Metastastic Tumors to the Lacrimal Gland from Distant Primary Cancer
Authors: Mombaerts Ilse , Rana Khizar , Verity David H. , Malhotra Raman , Poh Eugenie W. T. , Selva Dinesh
Published: December 2024

Purpose:

To characterize the clinical, radiological, and pathological features of patients with metastases to the lacrimal gland from distant primaries.

Methods:

Multicentre retrospective case series and a review of the literature of cases of metastases to the lacrimal gland.

Results:

We present 4 cases of lacrimal gland metastases, with the primaries being renal cell (n = 2) and breast (n = 2) carcinoma. The literature review identified 40 additional cases (19 male, mean age, range 21–84 years) of lacrimal gland metastasis. Based on these 44 cases, including 4 from the present study, 2 patterns of metastasis were identified: 23 cases (52.3%, 23/44) with lacrimal gland enlargement without bony erosion, and 21 cases (47.7%, 21/44) with associated bony erosion of the superolateral orbit of whom 12 (57.1%, 12/21) had intracranial extension. The most common primary for lacrimal gland metastasis without bony erosion was breast cancer (56.5%, 13/23), whereas hepatocellular carcinoma was the most common cause of lacrimal gland metastasis with bony erosion (52.4%, 11/21). Lacrimal gland metastasis was the first presentation of cancer in 15 cases (34.1%, 15/44) and was the first presentation of metastasis in 12 cases (27.3%, 12/44).

Conclusions:

Metastasis to the lacrimal gland is a potential cause of lacrimal gland enlargement. It may be the initial sign of distal occult cancer or occult metastatic disease. Different patterns of metastasis may be seen with different underlying primaries.
Relationship Between the Pain Intensity at the Time of the Hamstring Muscle Injury and the Hyperintense T2 Weighted Volume of the Hamstring Muscle Lesion Measured by MRI
Authors: Grange Sylvain , Plancher Ronan , Reurink Gustaav , Croisille Pierre , Edouard Pascal
Published: December 2024

Objectives:

The primary objective of this study was to analyze the correlation between the pain experienced at the time of a hamstring muscle injury and the hyperintense T2 weighted volume of the lesion measured on MRI. The secondary objectives were to analyze the differences in this pain with the lesion grade and the hamstring muscle head involved.

Design:

We performed a retrospective analysis of the data collected in a prospective, multicenter, noninterventional cohort study (HAMMER).

Patients:

A total of 61 patients were included in this analysis.

Interventions:

Patients with suspected hamstring muscle injury had an MRI after the injury.

Main outcomes measures:

They were evaluated for their pain intensity experienced at the time of injury with a Numeric Pain Rating Scale (NPRS) from 0 to 10.

Results:

There was a significant but weak correlation between the pain experienced at the time of hamstring muscle injury and the hyperintense T2 weighted volume (r = 0.287; P = 0.025). There were no significant differences in the pain according to the lesion grade (F(3,57) = 0.982; P = 0.408) nor according to the muscle involved (F(3,57) = 1.013; P = 0.394).

Conclusions:

Pain at the time of injury seemed to be weakly correlated with the extent of muscle lesion at medical imaging. Pain at the time of injury alone seems not enough to give us a clinical meaningful indication of the MRI hyperintense T2 weighted volume.
Implementation of an Opt-out and Rapid Point-Of-Care Syphilis Testing Program for Pregnant Patients Presenting to the Emergency Department
Authors: Stafford Irene A. , Bakunas Carrie , Haydamous Joe , Mosqueda Ana , Klausner Jeffrey D. , Mena Leandro , Blackwell Sean C.
Published: December 2024

Background

Adult and congenital syphilis rates are rising in the US. The aim of this pre- and post-implementation study was to determine whether implementation of an opt-out laboratory-based and rapid syphilis point-of-care testing program in the emergency department (ED) improves the detection and treatment of syphilis during pregnancy in a high-prevalence region.

Methods

This pre-and post-implementation study was conducted at the University of Texas Health Science Center, Houston, TX. During the pre-implementation phase (11/01/2023 - 02/29/2024), pregnant patients presenting to the ED underwent lab-based syphilis testing using the reverse algorithm only when clinically indicated. In the post-implementation phase (03/01/2024 - 06/25/2024), pregnant patients without prenatal care or with no documented syphilis result underwent opt-out syphilis testing using the Syphilis Health Check (SHC) point-of-care test and the lab-based reverse syphilis testing algorithm. Patients with positive syphilis test results were treated by providers. All results were confirmed with the lab-based test and patient follow up was scheduled.

Results

During the pre-implementation period, 302 pregnant patients presented to the ED, and only 6 (2%) underwent syphilis lab-based testing, none of which yielded positive results. In the post-implementation period, 322 pregnant patients presented to the ED and 202 (62.7%) were approached. Of these, 114 (56.4%) were tested using either the SHC or lab-based reverse algorithm (p < 0.001). Four patients tested positive for syphilis, indicating a prevalence of 3.5%.

Conclusions

An opt-out and rapid syphilis testing program for pregnant individuals visiting the ED increased syphilis screening from 2% to 56.4%, and detected syphilis that might have otherwise been missed.
Impact of Implementing a Grossing Tumor-margin Distance Threshold for Frozen Section in Oncologic Lung Surgery
Authors: Kordahi Manal , Gagné Andréanne , Abolfathi Hanie , Orain Michèle , Couture Christian , Desmeules Patrice , Trahan Sylvain , Pagé Sylvain , Vaucher Jonathan , Nicodème Frederic , Conti Massimo , Ugalde Figueroa Paula , Laliberté Anne-Sophie , Lamaze Fabien C. , Bossé Yohan , Joubert Philippe
Published: December 2024

Intraoperative frozen section (FS) examination of oncologic surgical specimens is frequently performed to ensure complete surgical resection. Data on the gross evaluation of surgical margins are limited. We recently published a study suggesting the use of a macroscopic 2.0 cm tumor-margin cutoff during intraoperative evaluation to decrease the number of unnecessary FS. This study aimed to validate the safety and the clinical impacts of implementing a 2.0 cm tumor-margin threshold for FS diagnosis in evaluating surgical margins during oncologic lung surgery. This retrospective analysis included patients who underwent lung resection for primary or metastatic neoplasms between 2018 and 2022 at the Institut Universitaire de Cardiologie et de Pneumologie de Québec, following the implementation of this practice. Clinicopathological data were retrieved from the medical files. Univariate and multivariate analyses were used to identify the variables associated with positive margins. This study included 1575 tumors in 1299 patients. FS evaluations were performed in 24.4% of patients. No positive margins were observed when the tumor-margin distance was >2.0 cm. The incidence rate of positive margins was 2.95%, with parenchymal margins being the most affected. Multivariate analysis identified the tumor-margin distance as a significant predictor of positive margin status. This practice led to a 79.9% reduction in FS evaluations without compromising the margin assessment accuracy or patient safety. A 2.0 cm tumor-margin distance threshold for intraoperative FS evaluation in oncologic lung surgery is safe and effective in reducing unnecessary FS evaluations while maintaining accurate margin assessments.
Quantum optical phase, rigged Hilbert spaces and complementarity
Authors: Bordon Khai , Vaccaro Joan A.
Published: December 2024

We place Loudon’s quantum treatment of optical phase in
The quantum theory of light
in its historical context, and outline research that it inspired. We show how it led Pegg and Barnett to their quantum phase formalism, explaining the challenges that they overcame to define phase operators and phase eigenstates rigorously. We show how the formalism essentially constructs an extended rigged Hilbert space that supports strong limits of the phase operators and includes their eigenstates. We identify the complementarity structure (consisting of mutually unbiased bases and generators of cyclical permutations) underpinning Pegg and Barnett’s general approach that gives a quantum-classical correspondence free of the ambiguity of Dirac’s commutator–Poisson bracket correspondence.

This article is part of the theme issue ‘The quantum theory of light’.
Gauge and unitary transformations in multipolar quantum optics
Authors: Babiker Mohamed
Published: December 2024

Multipolar quantum optics deals with the interaction of light with matter as a many-body bound system of charged particles where the coupling to electromagnetic fields is in terms of the multipolar electric polarization and magnetization. We describe two transformations applied to the conventional non-relativistic formalism, namely a gauge transformation applied directly to the fields at the Lagrangian stage and a unitary transformation applied to the old Hamiltonian. We show how such transformations lead to the same Power–Zienau–Woolley (PZW) formulation of the quantum electrodynamics (QED) of an overall electrically neutral many-body bound system of charges, including the internal motion as well as the gross dynamics of the centre of mass. Besides highlighting the utility of the multipolar formalism as a reliable and convenient platform in dealing with optical processes in atomic and molecular physics, it is shown how the analysis can also lead to the identification of the Röntgen effect arising from the gross motion of an electric dipole moment in a magnetic field and the Aharonov–Casher effect due to the motion of a magnetic dipole moment in an electric field. The importance of the two effects is pointed out in both experimental and theoretical contexts.

This article is part of the theme issue ‘The quantum theory of light’.
Non-classicality and the effect of one photon
Authors: Gerry Christopher C. , Birrittella Richard J. , Alsing Paul M. , Mimih Jihane , Knight Peter L.
Published: December 2024

The quantum interference effects of mixing the most non-classical states of light, number states, with the most classical-like of pure field states, the coherent state, are investigated. We demonstrate how the non-classicality of a single photon when mixed with a coherent field can transform the statistical properties of the output and further demonstrate that the entanglement of the output is independent of the coherent state amplitude.

This article is part of the theme issue ‘The quantum theory of light’.
Theory and application of cavity solitons in photonic devices
Authors: Oppo Gian-Luca , Firth William J.
Published: December 2024

Driven optical cavities containing a nonlinear medium support stable dissipative solitons, cavity solitons, in the form of bright or dark spots of light on a uniformly-lit background. Broadening effects due to diffraction or group velocity dispersion are balanced by the nonlinear interaction with the medium while cavity losses balance the input energy. The history, properties, physical interpretation and wide application of cavity solitons are reviewed. Cavity solitons in the plane perpendicular to light propagation find application in optical information processing, while cavity solitons in the longitudinal direction produce high-quality frequency combs with applications in optical communications, frequency standards, optical clocks, future GPS, astronomy and quantum technologies.

This article is part of the theme issue ‘The quantum theory of light’.
Intensity correlations in the Wigner representation
Authors: Shikhali Najafabadi Mojdeh , Sanchez-Soto Luis L. , Huang Kun , Laurat Julien , Le Jeannic Hanna , Leuchs Gerd
Published: December 2024

We derive a compact expression for the second-order correlation function

g

(
2
)

(
0
)

of a quantum state in terms of its Wigner function, thereby establishing a direct link between

g

(
2
)

(
0
)

and the state’s shape in phase space. We conduct an experiment that simultaneously measures

g

(
2
)

(
0
)

through direct photocounting and reconstructs the Wigner function via homodyne tomography. The results confirm our theoretical predictions.

This article is part of the theme issue ‘The quantum theory of light’.
The quantum theory of light
Authors: Barnett Stephen M. , Jeffers John
Published: December 2024

We present a brief introduction to the quantum theory of light as it is understood in the field of quantum optics. Our aim is not to review the topic, which would require a very extensive article (or even a book of several volumes) but rather to provide sufficient background to set the ideas in the following papers in their correct context.

This article is part of the theme issue ‘The quantum theory of light’.
Rapid long-range synaptic remodeling in hyperacute ischemic stroke
Authors: Chen Huanhuan , Wei Ye , Ruje Luminiţa , Wan Qi , Spivakov Mikhail , Glebov Oleg O.
Published: December 2024

Physiological mechanisms of the key hyperacute (0-24 hours) stage of stroke remain incompletely understood, hampering development of new stroke therapies. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe rapid region-specific patterns of synaptic remodeling in stroke, arising within 4 hours of onset. While the ischemic core exhibits profound structural and functional synaptic decline, synapses in the mildly ischemic penumbra largely retain their structure, decreasing synaptic function. Conversely, synapses in the contralateral cortex across the brain show widespread structural and functional increase. Mechanistically, hyperacute stroke triggers synaptic recruitment of NMDA receptors in the ischemic core and penumbra, while NMDA receptor blockade exacerbates structural synaptic decline in the penumbra and abolishes contralateral synaptic enhancement. Proteomic analysis confirms cross-brain synaptic strengthening and reveals emergence of metabolic rearrangement in the penumbra, while RNAseq indicates broad downregulation of synaptic gene expression in the penumbra. These findings identify brain-wide homeostatic synaptic rebalancing as a potential mechanism for rapid-response functional compensation in early stroke, highlighting the extent of brain resilience to acute perturbation.

Highlights

Stroke induces rapid long-range synaptic enhancement in the contralateral hemisphere

NMDAR signaling orchestrates short and long-range synaptic remodeling in stroke

Proteomics and RNAseq reveal details of region-specific synaptic remodeling

eTOC blurb

What happens to synaptic communication across the brain during the first hours of stroke is unclear. We find that while synapses at the center of the stroke quickly fall apart, those in the surrounding area are protected and those in the opposite hemisphere are rapidly strengthened by the activity of NMDA-type glutamate receptors.
Physical Interactions Drive Collective Thermoregulatory Behavior in Honey Bees
Authors: Lambert Casey E. , Vazquez Kyara , Nelson Zachary P. , Cook Chelsea N.
Published: December 2024

Social animals can coordinate complex behaviors, which can affect massive change on the environment. Within groups, individuals can sense the environment and communicate that information with others. Direct contact, like physical touch, is a key method of communication among social animals, and may be a mechanism to facilitate the coordination of collective behaviors that buffer environmental change. Here, we use a collective thermoregulatory fanning behavior in honey bees (Apis mellifera) to test the hypothesis that direct physical contact is necessary to perform this behavior. By modulating their ability to engage in physical contact, we establish that honey bee workers must touch each other to coordinate the fanning response. We then manipulated social density by changing the physical space the bees occupied to modulate likelihood of contact and found that in high social densities, honey bees are more likely to fan. Using video tracking, we then verified that bees in higher social density indeed have more direct physical interactions. This work identifies a mechanism of communication and potentially information synthesis in an ecologically relevant collective behavior. By understanding the ways in which animals communicate, we may be able to pinpoint the mechanisms of resilience that social insects evolved to manage a changing world.
FABP5 in Skin Macrophages Mediates Saturated Fat-Induced IL-1β Signaling in Obesity-Associated Psoriasis Development
Authors: Yu Jianyu , Hao Jiaqing , Yorek Matthew S. , Jiang Xingshan , Avellino Anthony , Liu Shanshan , Han Xiaochun , Shilyansky Jonathan , Wang Zhaohua , Jabbari Ali , Li Bing
Published: December 2024

High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFD-induced obesity on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs – saturated, monounsaturated, omega-6 and omega-3 fats – were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1β-producing macrophages, IL-17A-producing γδ T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1β/IL-17 signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1β/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1β/IL-17 axis, offering insights into the interplay between dietary fats, obesity and psoriasis.

Highlights

Saturated, but not unsaturated, high-fat diets (HFDs) drive the development of obesity-associated psoriasis.

Saturated fats enhance IL-1β/IL-17 signaling in psoriatic skin.

FABP5 mediates saturated fat-induced IL-1β signaling by promoting ATP production and release.

Deletion of FABP5 in macrophages alleviates the development of saturated HFD-associated psoriasis.

Graphic Abstract
Behavioral and metabolic effects of extended hippocampal overexpression of the myokine Irisin in an Alzheimer’s Disease mouse model
Authors: Borukhin Jacob A. , Kang Erin , Tomas Rodrigo F. , Wang Caoyuanhui , Trotz Arielle , Requejo Adrian , McIntyre Jeremy C. , Alviña Karina
Published: December 2024

Lifestyle interventions such as exercise are promising strategies to reduce the detrimental effects faced by aging populations. In particular, the exercise-induced myokine Irisin could act as a mediator of the positive effects of exercise, even as a potential therapeutic option for Alzheimer’s disease (AD). However, the fundamental roles of Irisin in counteracting AD neuropathology and other effects have not been fully determined. In addition, whether centrally produced Irisin has any effects is unclear. Here we examined the neurobehavioral effects of overexpressing Irisin directly in the hippocampus of an AD transgenic mouse line (TgCRND8), using adult male mice stereotaxically injected with Irisin-AAV vector. To further mimic chronic exercise, spatial memory and exploratory behaviors were assessed using the novel object recognition (NOR)/open field test (OFT) and Y-Maze tests after 8 weeks.

Our results showed that Irisin expression led to several behavioral changes, including increased grooming behavior and slightly improved spatial memory performance in short interval NOR test in Tg mice. In the Y-Maze test however, we observed an increase in time spent in familiar spaces, which could indicate heightened anxiety-like behaviors in mice injected with Irisin-AAV. In addition, we observed significant differences in body and liver size, and in circulating metabolites such as ketone bodies, that were differentially regulated in NTg or Tg mice.

Overall, our findings show important neurobehavioral effects of long-lasting overexpression of the exerkine Irisin in the hippocampus. Our results also raise questions about potential detrimental effects and thus warrant further studies to fully dissect how this exercise mediator affects the brain.
A biologically-inspired hierarchical convolutional energy model predicts V4 responses to natural videos
Authors: Oliver Michael , Winter Michele , Dupré la Tour Tom , Eickenberg Michael , Gallant Jack L.
Published: December 2024

V4 is a key area within the visual processing hierarchy, and it represents features of intermediate complexity. However, no current computational model explains V4 responses under natural conditions. To address this, we developed a new hierarchical convolutional energy (HCE) model reflecting computations thought to occur in areas V1, V2, and V4, but which consists entirely of simple- and complex-like units like those found in V1. In contrast to prior models, the HCE model is trained end-to-end on neurophysiology data, without relying on pre-trained network features. We recorded 313 V4 neurons during full-color nature video stimulation and fit the HCE model to each neuron. The model’s predicted optimal patterns (POPs) revealed complex spatiotemporal pattern selectivity in V4, supporting its role in representing space, time, and color. These findings indicate that area V4 is crucial for image segmentation and grouping operations that are essential for complex vision. Thus, responses of V4 neurons under naturalistic conditions can be explained by a hierarchical three-stage model where each stage consists entirely of units like those found in area V1.
Androgen stimulation rapidly reorganizes temporal 3D genome and epigenome states to trigger AR-mediated transcription in prostate cancer
Authors: Campbell Elyssa M. , Laven-Law Geraldine , Smith Grady , Peters Timothy J , Colino-Sanguino Yolanda , Moulder David , Du Qian , Jones Alicia , Giles Katherine A. , Khoury Amanda , Stirzaker Clare , Hickey Theresa A. , Mora Fatima Valdes , Clark Susan J. , Achinger-Kawecka Joanna
Published: December 2024

Introduction

Androgen receptor (AR)-mediated transcription drives prostate cancer progression and remains a key therapeutic target. AR is activated by androgens, translocating to the nucleus to bind DNA regulatory elements (AREs) and initiate transcription. This process involves co-regulatory proteins, pioneer factors like FOXA1, epigenetic modifications, and 3D chromatin interactions. However, the temporal coordination of AR and co-regulatory binding factors, epigenomic modifications, and 3D chromatin dynamics during AR-mediated transcription remains unclear.

Results

Using a time-course model of androgen stimulation in LNCaP prostate cancer cells, we integrated temporal multi-omics datasets into the MOFA+ framework to investigate AR-mediated transcriptional dynamics. Our analyses uncovered a critical role for rapid AR binding at gene promoters in driving nascent transcription of AR target genes. We demonstrated that AR binding is preceded by nucleosome H3K27 acetylation flanking androgen response elements, which are constitutively marked by FOXA1 binding. Notably, we identified a temporal early switch in nascent transcription post-androgen stimulation, from MYC to AR target genes, likely mediated by transient androgen-induced 3D chromatin interactions.

Significance

These findings reveal that androgen stimulation rapidly reorganizes 3D chromatin structure and differential MYC and AR transcription factor binding to trigger three distinct patterns of temporal epigenome states associated with the establishment of AR-mediated transcription in prostate cancer. These insights advance understanding of AR regulation in prostate cancer and contribute to a deeper understanding of the temporal relationship between MYC and AR transcriptional regulation in hormone-driven cancers.
FvM4K1, a Serine/Threonine Kinase and Ste20 Homolog Positively Regulates Fruit Size via Hippo Signalling Pathway in Woodland Strawberry (Fragaria vesca)
Authors: Gu Si , Nie Xinghua , Qin Ling , Xing Yu , Qi Baoxiu
Published: December 2024

Strawberry fruit size is critical for its marketability. However, organ size control is a complex process regulated by various signaling pathways. In animals, the Hippo signaling pathway acts as a negative regulator of organ size, with Ste20 kinase, a serine/threonine kinase being a key component. Mutation in Ste20 causes excessive cell proliferation and enlarged organs. In this study, FvM4K1, a Ste20-like kinase from woodland strawberry (Fragaria vesca), is identified. FvM4K1 partially restores defects in a yeast Ste20 mutantste20Δand fully rescues growth in Arabidopsis mutantatsik1-4lacking its Ste20 homolog, AtSIK1, underscoring its functional conservation. Downregulation FvM4K1 by RNAi in woodland strawberry leads to fruits and smaller plants resulting from reduced cell size and number, while overexpression increases organ size, indicating a positive role in fruit and organ size control which contrasts the negative role of Ste20 in other organisms. FvM4K1 auto-phosphorylates, with Lys269 and Thr396 being critical for its function. FvM4K1 interacts with FvMOB1A and FvMOB1B, components of the Hippo signalling pathway, and phosphorylates them at Thr35 and Thr36, respectively. These findings provide novel insights into the mechanisms underlying fruit and organ size control in woodland strawberry and contribute to our understanding of the Hippo signalling pathway in higher plants, a pathway that remains largely unexplored. It also opens new avenues for exploring the regulatory function of Hippo pathway in plant development and potentially inform biotechnological strategies for crop improvement.
Choices of regulatory logic class modulate the dynamical regime in random Boolean networks
Authors: Sil Priyotosh , Mitra Suchetana , Martin Olivier C. , Samal Areejit
Published: December 2024

Random Boolean networks (RBNs) have been widely explored as models for understanding complex systems, in particular gene regulatory networks (GRNs). Stability (order) and instability (chaos), critical characteristics of any dynamic system, have naturally been a central focus in RBN research. Several measures have previously been introduced to assess stability, e.g., via damage spreading or via statistical properties of attractors such as their number, lengths or basin sizes. Undoubtedly, network topology plays an important role in shaping the dynamics of RBN. Another key factor influencing the dynamics is the Boolean functions (BFs) assigned to each node. In this work, we conduct a systematic investigation to examine the influence of five different classes of BFs on the dynamics of RBNs. By employing various dynamical stability measures, we show that biologically meaningful BFs consistently drive the dynamics toward the stable regime compared to random BFs. This observation holds across networks with varying size, connectivity, and degree distributions. Additionally, we show that the change in the values of our stability measures with increasing connectivity or size of RBNs is different across the BF classes. For most observables, random BFs change the values significantly, pushing the dynamics toward a more chaotic regime with increasing connectivity or network size. In contrast, biologically meaningful BFs show very minimal fluctuations for most stability measures. These findings emphasize the advantage of restricting to biologically meaningful classes in the reconstruction and modeling of biological systems within Boolean framework.
Brain Ischemia in Alzheimer’s disease counteracts the Disruption of the Blood Brain Barrier: A Hypothesis Investigated with a Lumped Parameter Model
Authors: Bateman Grant A , Bateman Alexander R
Published: December 2024

Background

In normal pressure hydrocephalus (NPH) there is blood brain barrier (BBB) disruption, which should increase the CSF formation rate (CSFfr)and therefore the intracranial pressure (ICP). However, the ICP is normal in NPH. A lumped parameter study suggested that the CSFfrcould be reduced in this condition if the BBB disruption was moderated by a reduction in the capillary transmural pressure (TMP) secondary to arteriolar constriction. In early Alzheimer’s disease (AD), there is BBB disruption, reduced ICP and global ischemia. This raises the possibility that the same physiology may be occurring in AD as occurs in NPH.

Objective

This hypothesis can be analyzed further using a lumped parameter hydrodynamic model we have developed.

Methods

A lumped parameter model previously used to describe the hydrodynamics of NPH was modified to investigate the effects of changes in CSF pressure and blood flow in patients with mild cognitive impairment (MCI) and AD.

Results

The model indicates the capillary TMP is normal in MCI but decreases as AD progresses. Removing CSF in AD patients during a tap test initially increases the capillary TMP. The brain in AD responds to a tap test by increasing its level of ischemia and this reduces the capillary TMP.

Conclusions

A hypothesis is put forward that the BBB disruption in AD is partially mitigated by the brain making itself ischemic. Modelling gives support to this hypothesis. The model can explain the development of ischemic neuronal loss and amyloid accumulation secondary to glymphatic flow disruption as AD progresses.
ASMS: finding allele specific methylation in human genomes without phasing
Authors: Raineri Emanuele , Esteve Marco Miguel Ángel , Esteve Codina Anna
Published: December 2024

Motivation

Allele-specific methylation (ASM) refers to differential DNA methylation patterns between two alleles at a given locus. This phenomenon is often driven by genetic variants, such as single nucleotide variants (SNVs), which influence methylation incisby affecting transcription factor or methylation regulator binding, leading to allele-specific differences. Understanding ASM is critical for elucidating gene regulation, as it impacts gene expression and contributes to normal biological variation as well as disease processes, including cancer [1] and autoimmune disorders [2],[3].

Another key driver of ASM is genomic imprinting, an epigenetic mechanism in which gene expression is regulated in a parent-of-origin-specific manner. Imprinted regions, marked during gametogenesis and maintained through cell divisions, are essential for growth, development, and metabolism. Dysregulation of imprinting is associated with developmental and metabolic disorders, such as Prader-Willi and Angelman syndromes, and certain cancers.

Detecting ASM across the genome remains challenging due to its tissue- and cell-specific nature and the technical difficulty of phasing reads to assign methylation patterns to specific alleles. Current ASM detection pipelines (e.g., [4])) often require phasing via genetic variants, a computationally intensive process that is limited in regions with low heterozygosity.

Results

To address these limitations, we developed asms (Allele-Specific Methylation Scanner), a tool designed to detect ASM directly from methylation data without the need for prior phasing. asms offers a faster and complementary approach to uncovering the regulatory effects of ASM, particularly in genomic regions where genetic variants or imprinting play a critical role.

For demonstration purposes we leverage the fact that reads generated by Oxford Nanopore (ONT) technology measure sequence and methylation status at once, but the same software can be used with other sequencing technologies.

asmscan check thousands of loci in a short time. The initial list of loci to examine can be given by the user, or generated byasmsthrough a genomic scan. Theasms clustersubcommand separates the reads based on methylation.

If phasing results are available,asmscan use them to verify whether distinct alleles correspond to distinct base modifications patterns. We benchmark our software using publicly available Ashkenazi trio data [5].

Implementation and availability

asmsis implemented inrustandpython. The software is available athttps://github.com/ecmra/asms.
Pharmacophore-guided de novo drug design with diffusion bridge
Authors: Wang Conghao , Rajapakse Jagath C.
Published: December 2024

De novodesign of bioactive drug molecules with potential to treat desired biological targets is a profound task in the drug discovery process. Existing approaches tend to leverage the pocket structure of the target protein to condition the molecule generation. However, even the pocket area of the target protein may contain redundant information since not all atoms in the pocket is responsible for the interaction with the ligand. In this work, we propose PharmacoBridge, a phamacophore-guidedde novodesign approach to generate drug candidates inducing desired bioactivity via diffusion bridge. Our method adapts the diffusion bridge to effectively convert pharmacophore arrangements in the spatial space into molecular structures under the manner ofSE(3) -equivariant transformation, providing sophisticated control over optimal biochemical feature arrangements on the generated molecules. PharmacoBridge is demonstrated to generate hit candidates that exhibit high binding affinity with potential protein targets.
Expanding the diversity of nitroxide-based paramagnetic probes conjugated to non-canonical amino acids for SDSL-EPR applications
Authors: Bizet Maxime , Balázsi Áron , Biaso Frédéric , Byrne Deborah , Etienne Emilien , Guigliarelli Bruno , Urban Philippe , Dorlet Pierre , Truan Gilles , Gerbaud Guillaume , Kálai Tamás , Martinho Marlène
Published: December 2024

Understanding protein structure requires studying its dynamics, which is critical to elucidating its functional role. Over time, biophysical techniques have revolutionized this field, offering remarkable insights into the structure-function relationship. Among these, Site-Directed Spin Labelling (SDSL) combined with Electron Paramagnetic Resonance (EPR) is a powerful method delivering structural data at the residue level, irrespective of protein size or environment. Traditional nitroxide labels, which target cysteine residues, often face limitations when these residues are essential for protein structure or function. To address this, alternatives have been proposed as the use of non-canonical amino acids (ncaa) coupled with specific nitroxide labels. This study introduces14N-HO-5223, a novel nitroxide label specific to thepAzPhe ncaa, alongside its15N-derivative. These labels were grafted at two sites of the model protein, the diflavin Cytochrome P450 reductase. For comparative purpose, two already reported labels were also used. Continuous wave (cw) EPR spectroscopy validated the HO-5223 label as an effective reporter of protein dynamics. Additionally, Double Electron-Electron Resonance (DEER) measurements provided distance distributions between the semi-quinone FMNH•state of the CPR and all nitroxide labels. These results expand the toolkit of the ncaa-nitroxide pairs, enabling EPR-based structural studies of proteins where cysteine modification is impractical, further advancing our ability to decode protein dynamics and function.
Microphysiological uremia model reveals biophysical potentiators of vascular dysfunction
Authors: Rathod Mitesh , Huang Stephanie A. , Aw Wen Yih , Doherty Elizabeth L. , Meehan Sara M. , Roy-Chaudhury Prabir , Polacheck William J.
Published: December 2024

Cardiovascular disease is a leading cause of mortality in individuals with chronic kidney disease. Hypertension, common among patients with chronic kidney disease, is a major contributor to both kidney damage and the heightened cardiovascular risk in these patients. Advanced chronic kidney disease is associated with elevated levels of circulating uremic toxins, particularly indoxyl sulfate and p-cresyl sulfate, and are known to exacerbate cardiovascular risk by promoting inflammatory processes, including monocyte adhesion, rolling, and extravasation. However, despite the established link between chronic kidney disease and cardiovascular disease, the specific role of uremic toxins in monocyte-endothelial interactions in hypertensive settings remains largely underexplored. In this study, we developed a 3D microfluidic model to examine the effects of indoxyl sulfate on monocyte adhesion and extravasation across engineered microvessels embedded in collagen hydrogels with different densities under controlled luminal pressure. We found that elevated pressure alone significantly enhanced monocyte adhesion and extravasation, regardless of matrix density, and that the uremic environment further increased these effects. Additionally, denser hydrogels primed THP-1 monocyte cells toward a pro-inflammatory like phenotype with reduced phagocytic capacity, while softer hydrogels induced an anti-inflammatory like phenotype with enhanced phagocytosis. However, exposure to the uremic environment diminished phagocytosis and shifted cells toward a pro-inflammatory like state, irrespective of matrix density. The presented approach has the potential to experimentally dissect multiple factors that contribute to elevated cardiovascular risks in chronic kidney disease patients and improve the understanding of mechanisms involved in monocyte dynamics in chronic kidney disease- related cardiovascular disease.
Sex-dependent influence of major histocompatibility complex diversity on fitness in a social mammal
Authors: Schubert Nadine , Nichols Hazel J. , Mwanguhya Francis , Businge Robert , Kyambulima Solomon , Mwesige Kenneth , Hoffman Joseph I. , Cant Michael A. , Winternitz Jamie C.
Published: December 2024

Parasite infections affect males and females differently across a wide range of species, often due to differences in immune responses. Generally, females tend to have stronger immune defenses and lower parasite loads than males. The major histocompatibility complex (MHC) plays a crucial role in the adaptive immune response, and extensive research has explored how variation in this region influences infection and fitness outcomes. However, studies of sex-specific relationships between MHC variation and infection are scarce, perhaps because MHC genes are located on the autosomes, which are shared by both sexes. Here, we provide evidence of sexually antagonistic selection in a wild, group-living mammal—the banded mongoose. Using genetic and life history data collected from over 300 individuals across 25 years, we found that particularly MHC class I (MHC-I) but also MHC class II (MHC-II) diversity influence lifetime reproductive success differently in males and females. Specifically, higher MHC diversity is linked to increased fitness in males but decreased fitness in females. Furthermore, MHC diversity did not differ between the sexes, indicating an unresolved genetic sexual conflict. Our findings demonstrate that sexually antagonistic selection acts on the MHC and may operate across both MHC classes but differently. This study contributes to the growing body of evidence that sex is a significant factor in shaping host immunity and fitness.