bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Ankle-Foot Orthoses for Patients with Weakness of the Plantarflexors and Dorsiflexors: Biomechanical Comparison of Different Orthotic Concepts
Authors: Burkhardt Meike , Schmalz Thomas , Drewitz Heiko , Kannenberg Andreas , Bellmann Malte
Published: November 2024

Introduction

Weakness of plantarflexor and dorsiflexor muscles is a complex individual condition and can result in pathological gait, such as crouch gait or knee hyperextension. Affected patients can be supported with ankle-foot orthoses (AFOs) to improve gait and safety.

Objective

This study aims to compare three orthotic ankle joint designs in AFOs for patients with muscle weakness in the plantarflexors and/or dorsiflexors: a conventional hinged ankle joint with rigid stops (CAJ), a jointless orthosis (JLO), and a reactive-dynamic ankle joint with adjustable spring modules (RDA).

Study Design

Seven patients with plantarflexor and/or dorsiflexor muscle weakness tested three orthosis configurations in randomized order during a single session.

Methods

Biomechanical gait analysis was performed during standing and walking on level ground and up and down 10° slopes. The main outcomes were ground reaction forces, joint angles, moments, and power at the ankle, knee, and hip joints. Mean values of outcome measures for patients and values of an able-bodied control group were compared with nonparametric analyses of variance and pairwise post hoc tests.

Results

Throughout all motion tasks, statistically significant differences (P < 0.05) were predominantly found in ankle and knee joint kinematics between RDA and CAJ, as well as between JLO and CAJ, whereas only few differences were found between RDA and JLO.

Conclusions

For this patient group, RDA enabled the most physiological gait, with outcomes measure values closest to those of the able-bodied control group, and the best perception of support for an active lifestyle and physically demanding activities. In less physically demanding situations, such as short walking distances and even surfaces, JLO also showed sufficient support for physiological gait and may be an adequate orthosis for patients living with supportive infrastructure or a more sedentary lifestyle. CAJ restricted physiological movements, showed the highest deviations from the values of the able-bodied controls in most activities, and provides the least comfort for patients in the tested situations.

Clinical Relevance Statement

Determining the best possible orthotic care and support for different patient groups is essential to enable independence, safety, and comfort during activities of daily living based on individual requirements.
3.0-Tesla MRI Observation at Return to Play After Hamstring Injuries
Authors: Zein Muhammad Ikhwan , Reurink Gustaaf , Suskens Jozef J. M. , Monte Jithsa R. C. , Smithuis Frank F. , Buckens Stan , Maas Mario , Tol Johannes L.
Published: November 2024

Objective:

To describe 3.0-Tesla (T) magnetic resonance imaging (MRI) findings of hamstring muscles in clinically recovered athletes who were cleared for return to play (RTP).

Design:

Prospective observational study.

Setting:

Hospital.

Participants:

Athletes (amateur and professional) who were cleared for RTP after hamstring injury. Fifty-eight participants were included in the analysis.

Independent Variables:

3-T MRI at baseline (within 7 days from initial injury) and MRI at RTP (within 10 days of RTP).

Main Outcome Measures:

Injury location, grade of injury (modified Peetrons and British Athletics Muscle Injury Classification/BAMIC), presence and the extent of intramuscular signal abnormality, intramuscular tendon disruption, and thickness. Reinjuries within 1 year of RTP were recorded.

Results:

Magnetic resonance images at RTP showed that 55 (95%) participants had intramuscular increased signal intensity (edema) and 44 (76%) participants had intramuscular abnormal low-signal intensity (suggesting fibrosis) on MRI. There was an overall reduction of injury grades according to the modified Peetrons and BAMIC classification at initial injury to RTP. Three (5%) participants had no abnormal signal intensities (grade 0 or grade 0A) on MRI at RTP. Intramuscular tendon disruption, waviness, and tendon thickening were present at RTP in, respectively, 22 (38%), 15 (26%), and 36 (62%). We recorded 3 (5%) reinjuries.

Conclusions:

At RTP, 3.0-T MRI shows high percentages of MRI abnormalities (edema, fibrosis, and intramuscular tendon disruption and thickening). We conclude that complete normalization of 3.0-T MRI is not expected for RTP decision after a hamstring injury. Its possible association with reinjury risk has to be determined in larger cohorts.
Musculoskeletal Soreness Location and Intensity in Soccer Athletes Across Multiple Seasons
Authors: Pexa Brett S. , Blue Malia N. M. , Barczak-Scarboro Nikki E. , Taylor Jeffrey B. , Johnston Christopher D. , Ford Kevin R.
Published: November 2024

Objective:

To compare soreness location and intensity between male and female soccer athletes across 2 competitive seasons.

Design:

Descriptive Cohort Study.

Setting:

Collegiate Sports Medicine Facility.

Participants:

Forty male and 42 female collegiate soccer athletes.

Intervention:

Season-long soccer trainings and games.

Main Outcome Measures:

Athletes reported perceived soreness location and intensity daily. χ2 analysis and linear mixed effect models were used to compare soreness locations and intensities by sex.

Results:

Male and female soccer athletes reported similar number of soreness instances, but male soccer athletes reported soreness more frequently at the ankle, foot, hip, pelvis, and posterior thigh. Female soccer athletes reported soreness more frequently at the anterior leg, anterior thigh, and knee. There was no significant difference in soreness intensity between sexes at any body location (P = 0.86). When collapsed across sex, the frequency of anterior thigh soreness was higher at preseason (7.49%, CI: 5.46-9.52) than at midseason (4.55%, CI: 2.52–6.57; t = −2.94, P = 0.023) and at postseason (3.00%, CI: 0.76-5.23; t = −3.74, P < 0.001). There was also a significant difference in hip soreness frequency between the preseason (2.35%, CI: 1.32-3.33) and the postseason time points (0.52%, CI: −0.73% to 1.67%; t = −2.68, P = 0.023).

Conclusions:

Male and female athletes differ in the locations of their lower extremity soreness. However, lower extremity soreness intensity does not differ between sexes. Soccer athletes report soreness more frequently during the preseason and midseason than during the postseason. With tools to measure daily soreness location and intensity, clinicians could create targeted interventions to reduce soreness and limit its negative affect.
Nurse-Led Mobile App Effect on Quality of Life in Breast Cancer Patients After Surgery: Nonrandomized Controlled Prospective Cohort Study (Step 3)
Authors: Aydin Aydanur , Gürsoy Ayla
Published: November 2024

Background

Following surgery, women with breast cancer (BC) frequently experience emotional and physiological negative consequences.

Objective

To evaluate the effect of a nurse-led mobile app (NL-Mapp) intervention on quality of life (QoL) in patients after surgery for BC.

Methods

This single-center, 12-month, nonrandomized controlled trial, with 2 parallel groups, represents the final stage of 3-step research. In this study, women were assigned to either the intervention (n = 45) or control (n = 45) group. The intervention group participated in the NL-Mapp, whereas participants in the control group received standard care. The main outcomes were measured using the Functional Assessment of Cancer Therapy—Breast at 3 time points (baseline and 1 and 12 months after the intervention). Clinical Trial number: NCT06505538

Results

The intervention participants reported significant improvement in physical well-being, emotional well-being, and the BC-specific subscale compared with the control group at the 1-month postsurgery mark. Equally noteworthy, at the 1-year follow-up, consistent improvements were observed across all QoL subscale scores for the intervention group, except for the BC-specific subscale for additional concerns.

Conclusion

Our study revealed a notable enhancement in the QoL among postoperative women with BC who utilized the NL-Mapp. This program emerges as an effective intervention for providing short-term and longer-term supportive care to women affected by BC, leading to tangible improvements in their QoL.

Implication for Nursing

The study’s findings offer valuable evidence supporting the integration of mobile health services into clinical and transitional nursing care.
Intraoperative Surgical Guidance for DIEP Flap Harvest using Augmented Reality
Authors: Edgcumbe Philip , Jiang Tony , Ho Joshua F. , Martin Michael L. , Stein Michael J. , Isaac Kathryn V.
Published: November 2024

Augmented reality (AR) systems for surgical navigation provides the capability to project preoperative CT scans and segmented anatomical structures directly into the surgeon’s field of view, along with virtual displays akin to traditional monitors. Utilizing the Meta Quest 3 consumer AR headset, we found that it can achieve clinically acceptable accuracy in surgical navigation for deep inferior epigastric perforator (DIEP) surgeries. Notably, the Quest 3 can operate independently thanks to a novel registration technique employing hand tracking, suitable for use in sterile environments.

The DIEP flap is a widely favored option for autologous breast reconstructions. Intraoperatively, the perforator arteries are selected to maximize tissue perfusion and minimize donor site morbidity. Conventionally, preoperative CT angiograms are used to locate perforators and visualize vessel courses, thus reducing DIEP flap harvest time and complication rates. Though, there are currently very limited means to reliably translate information found on preoperative imaging for use in the operating theater.

The Meta Quest 3 was trialed in three DIEP flap surgeries by displaying segmented deep inferior epigastric arteries and DIEP arteries during preoperative and intraoperative phases of surgery. The AR projections facilitated the visualization of the DIEP arteries and efficient pedicle dissection by guiding the placement and length of the fascial incision. Furthermore, this work supports the hypothesis that AR will improve flap design, reduce harvest time, and improve safety during DIEP flap harvesting.
Vaccine hesitancy and other challenges to sexually transmitted infection vaccine acceptance
Authors: Footman Alison , Griner Stacey B.
Published: November 2024

Purpose of review

Development of vaccines that protect against sexually transmitted infections (STIs), including for chlamydia, gonorrhea, and syphilis, has progressed greatly over the past decade. However, little research has been conducted to examine STI vaccine acceptance and hesitancy and how these factors may impact future uptake. This review examines literature that could provide additional insights into factors that would impact STI vaccine acceptance and hesitancy.

Recent findings

Vaccine hesitancy remains a threat to the uptake of future STI vaccines despite recent findings that highlight high levels of acceptability. Vaccine characteristics including side effects postvaccination and cost could impact future uptake of these vaccines. Accurate information about the benefits of vaccination and the vaccine development process could help to improve vaccine acceptance.

STI vaccine development is progressing, leading to great promise that a chlamydia, gonorrhea, or syphilis vaccine will one day be available. However, data is limited on factors that could impact vaccine acceptance, hesitancy, and uptake. This research is instrumental in creating policies, programming and vaccination campaigns that could impact acceptance and uptake along with affordability and accessibility. Additional research is needed to better promote STI vaccines.
Abdominal Fascial Plication and the Risk of Venous Thromboembolism in Abdominoplasty Patients
Authors: Swanson Eric
Published: November 2024

Background

Repair of the abdominal fascia at the time of abdominoplasty is a valuable method to improve the contour of the abdomen. However, this maneuver has been linked to an increased risk of venous thromboembolism (VTE). This review was undertaken to evaluate the evidence.

Methods

An electronic literature review was conducted to identify publications on the subject of abdominal fascial repair during abdominoplasty and VTE risk. Key words included abdominoplasty, fascial plication, intra-abdominal pressure, and venous thrombosis.

Results

Three large clinical studies were identified. One retrospective study using matched comparisons reported nearly identical VTE rates for patients treated with and without abdominal fascial plication (1.5% vs 1.7%). Another retrospective study reported significantly more VTEs (2.3%) in abdominoplasty patients undergoing fascial repair compared with panniculectomy patients who did not undergo fascial plication (0.36%). The author also recommended a modified Caprini score, adding fascial repair as a risk factor. Only 1 prospective study reported a large number of consecutive plastic surgery outpatients evaluated with Doppler ultrasound. This group included 188 abdominoplasty patients, all treated with fascial plication and without muscle paralysis. Only 1 VTE was diagnosed on the day after abdominoplasty (0.5%).

Discussion

Retrospective studies are susceptible to confounders and confirmation bias. Caprini scores do not have a scientific foundation. Chemoprophylaxis increases the risk of bleeding without reducing the risk of VTE.

Conclusions

The best available evidence supports performing a fascial repair. An effective and safe alternative to Caprini scores and chemoprophylaxis is avoidance of muscle paralysis and early detection of VTEs using ultrasound screening.
Management of Temporoparietal Flap on Difficult Facial Deformities With Minimal Donor Site Morbidity
Authors: Horoz Ugur , Tellioglu Ali Teoman
Published: November 2024

The aim of this study is to investigate the use of the temporoparietal fascial flap (TPFF) in the repair of tissue defects in the head and neck region. TPFF is a preferred method among surgeons due to its thin and flexible structure and its strong vascular structure supplied by the superficial temporal artery. In the study, the operations performed on a total of 21 patients and the results of these operations were analyzed. TPFF has been used in the repair of facial and neck deformities caused by various reasons such as trauma, infection, Romberg syndrome and skin tumors. It has been reported that TPFF, which can be applied as a pedicled or free flap, gives aesthetically satisfactory results without significant complications on the flap. However, minor complications such as partial flap loss, hematoma and skin graft loss were observed in four patients. These complications were resolved by surgical interventions. In conclusion, TPFF is defined as an effective and safe option for the repair of various tissue defects with minimal donor-site morbidity. Thanks to the thin and flexible structure of the flap, aesthetic harmony is achieved although the risk of complications remains at low levels. Therefore, TPFF stands out as an important option for surgeons, especially in the elimination of facial contour irregularities and repair of sensitive tissue areas.
Cardiac autonomic neuropathy: impact on severe hypoglycemic unawareness and orthostatic hypotension in diabetic dysautonomia, a case series and review
Authors: Wu Chaoneng , Devireddy Rakesh , Zazaian Andrew , Kambhatla Sujata , Alzohaili Opada , Saad Chadi
Published: November 2024

Diabetic autonomic neuropathy (DAN) and its associated cardiovascular autonomic neuropathy (CAN) can lead to potentially fatal complications. We analyzed two distinct cases of DAN/CAN based on comprehensive cardiovascular autonomic reflex tests (CARTs). Case 1 involves a 27-year-old patient with T1DM suffering from recurrent severe hypoglycemic unawareness due to DAN. After implementing an automated insulin delivery system, the glucose management improved significantly. Case 2 describes a 60-year-old patient with type 2 diabetes experiencing debilitating orthostatic hypotension. The initiation of Midodrine and Fludrocortisone markedly improved symptoms and capacity of daily activities. This observational study highlights the critical yet frequently overlooked severe manifestations of DAN/CAN, specifically hypoglycemic unawareness and orthostatic hypotension. CARTs play a pivotal role in confirming the diagnosis and guiding therapeutic decisions. Tailored interventions, including advanced technologies like automated insulin delivery systems for T1DM and pharmacotherapy targeting neurogenic orthostasis, can significantly improve patient outcomes and quality of life.
Linking planar polarity signalling to actomyosin contractility during vertebrate neurulation
Authors: Novotna Sarka , Maia Lorena Agostini , Radaszkiewicz Katarzyna Anna , Roudnicky Pavel , Harnos Jakub
Published: November 2024

Actomyosin contractility represents an ancient feature of eukaryotic cells participating in many developmental and homeostasis events, including tissue morphogenesis, muscle contraction and cell migration, with dysregulation implicated in various pathological conditions, such as cancer. At the molecular level, actomyosin comprises actin bundles and myosin motor proteins that are sensitive to posttranslational modifications like phosphorylation. While the molecular components of actomyosin are well understood, the coordination of contractility by extracellular and intracellular signals, particularly from cellular signalling pathways, remains incompletely elucidated. This study focuses on WNT/planar cell polarity (PCP) signalling, previously associated with actomyosin contractility during vertebrate neurulation. Our investigation reveals that the main cytoplasmic PCP proteins, Prickle and Dishevelled, interact with key actomyosin components such as myosin light chain 9 (MLC9), leading to its phosphorylation and localized activation. Using proteomics and microscopy approaches, we demonstrate that both PCP proteins actively control actomyosin contractility through Rap1 small GTPases in relevant
in vitro
and
in vivo
models. These findings unveil a novel mechanism of how PCP signalling regulates actomyosin contractility through MLC9 and Rap1 that is relevant to vertebrate neurulation.
The time between symptom onset and various clinical outcomes: a statistical analysis of MERS-CoV patients in Saudi Arabia
Authors: Althobaity Yehya M. , Alkhudaydi Muhammad H. , Hill Edward M. , Thompson Robin N. , Tildesley Michael J.
Published: November 2024

In this study, we investigate the impact of demographic characteristics on Middle East respiratory syndrome coronavirus (MERS-CoV) cases in Saudi Arabia, specifically focusing on the time intervals between symptom onset and key events such as hospitalization, case confirmation, reporting and death. We estimate these intervals using data from 2196 cases occurring between June 2012 and January 2020, partitioning the data into four age groups (0–24 years, 25–49 years, 50–74 years and 75–100 years). The duration from symptom onset to hospitalization varies between age cohorts, ranging from 4.03 to 4.75 days, with the 75–100 age group experiencing the longest delay. The interval from symptom onset to case confirmation spans 5.83–8.24 days, and again, the 75–100 age group faces the lengthiest delay. The interval from symptom onset and case reporting ranges from 7.0 to 9.8 days, with the 75–100 age group experiencing the longest delay. The period from symptom onset to death varies across age groups (12.3–16.1 days), with elevated mortality rates during outbreaks. Importantly, we observe age-based differences in the risk of hospitalization and other measures of infection severity, including the probability of death conditional on hospitalization. Careful quantification of epidemiological characteristics, including inference of key epidemiological periods and assessments of differences between cases of different ages, plays a crucial role in understanding the progression of MERS-CoV outbreaks and formulating effective public health strategies to mitigate their impact.
Synthesis and biological evaluation of diclofenac acid derivatives as potential lipoxygenase and α-glucosidase inhibitors
Authors: Sardar Asma , Abid Obaid-ur-Rahman , Rehman Wajid , Rasheed Liaqat , Alanazi Mohammed M. , Daud Saima , Rafiq Muhammad , Wadood Abdul , Shakeel Muhammed
Published: November 2024

Inflammation is a complex physiological response associated with the onset and progression of various disorders, including diabetes. In this study, we synthesized a series of diclofenac acid derivatives and evaluated their potential anti-diabetic and anti-inflammatory activities. The compounds were specifically assessed for their ability to inhibit 15-lipoxygenase (15-LOX) and α-glucosidase enzymes. The structures of synthesized derivatives were confirmed through
1
H nuclear magnetic resonance (NMR),
13
C-NMR and high-resolution mass spectrometry (electron ionization) analysis. All these synthesized derivatives exhibited varying degrees of inhibitory activity against LOX, when compared with standard drugs, compounds
5a
(half-maximal inhibitory concentration (IC
50
) 14 ± 1 µM),
5b
(IC
50
61 ± 1 µM) and
7c
(IC
50
67 ± 1 µM) showed good activity against the LOX enzyme. While the α-glucosidase inhibitory results revealed that most of the compounds exhibited significant activity when compared with the standard drug acarbose (376 ± 1 µM). The most potent compounds as α
-
glucosidase inhibitors were
7b
(3 ± 1 µM),
4b
(5 ± 1 µM),
7a
(7 ± 1 µM) and
8b
(11 ± 1 µM). All these active compounds were found to be least toxic and maintained the mononuclear cells viability at 96–97% compared with that of controls as determined by multi-transaction translator assay. Molecular docking studies further reiterated the significance of these ‘lead’ compounds with great potential against the target enzymes in the process of drug discovery.
Assessing the spatial scale of synchrony in forest tree population dynamics
Authors: Chisholm Ryan A. , Fung Tak , Anderson-Teixeira Kristina J. , Bourg Norman A. , Brockelman Warren Y. , Bunyavejchewin Sarayudh , Chang-Yang Chia-Hao , Chen Yu-Yun , Chuyong George B. , Condit Richard , Dattaraja Handanakere S. , Davies Stuart J. , Ediriweera Sisira , Ewango Corneille E. N. , Fernando Edwino S. , Gunatilleke I. A. U. Nimal , Gunatilleke C. V. Savitri , Hao Zhanqing , Howe Robert W. , Kenfack David , Yao Tze Leong , Makana Jean-Remy , McMahon Sean M. , Mi Xiangcheng , Bt. Mohamad Mohizah , Myers Jonathan A. , Nathalang Anuttara , Pérez Álvaro J. , Phumsathan Sangsan , Pongpattananurak Nantachai , Ren Haibao , Rodriguez Lillian J. V. , Sukumar Raman , Sun I-Fang , Suresh Hebbalalu S. , Thomas Duncan W. , Thompson Jill , Uriarte Maria , Valencia Renato , Wang Xugao , Wolf Amy T. , Zimmerman Jess K.
Published: November 2024

Populations of forest trees exhibit large temporal fluctuations, but little is known about the synchrony of these fluctuations across space, including their sign, magnitude, causes and characteristic scales. These have important implications for metapopulation persistence and theoretical community ecology. Using data from permanent forest plots spanning local, regional and global spatial scales, we measured spatial synchrony in tree population growth rates over sub-decadal and decadal timescales and explored the relationship of synchrony to geographical distance. Synchrony was high at local scales of less than 1 km, with estimated Pearson correlations of approximately 0.6–0.8 between species’ population growth rates across pairs of quadrats. Synchrony decayed by approximately 17–44% with each order of magnitude increase in distance but was still detectably positive at distances of 100 km and beyond. Dispersal cannot explain observed large-scale synchrony because typical seed dispersal distances (<100 m) are far too short to couple the dynamics of distant forests on decadal timescales. We attribute the observed synchrony in forest dynamics primarily to the effect of spatially synchronous environmental drivers (the Moran effect), in particular climate, although pests, pathogens and anthropogenic drivers may play a role for some species.
The nature of label-induced categories: preverbal infants represent surface features and category symbols
Authors: Pomiechowska Barbara , Takács Szilvia , Volein Ágnes , Parise Eugenio
Published: November 2024

Humans categorize objects not only based on perceptual features (e.g. red, rounded), but also function (e.g. used to transport people). Category membership can be communicated via labelling (e.g. ‘apple’, ‘vehicle’). While it is well established that even preverbal infants rely on labels to learn categories, it remains unclear what is the nature of those categories: whether they simply contain sets of visual features diagnostic of category membership, or whether they additionally contain abstract category markers or symbols (e.g. linguistic in the form of category labels or non-linguistic). To address this question, we first used labelling to teach two novel object categories, each composed of unfamiliar visually unrelated objects, to adults and nine-month-olds. Then, we assessed categorization in an electroencephalography category-oddball task. Both adults and infants displayed stronger neural responses to the infrequent category, which, in the absence of visual features shared by all category members, indicates that the categories they set up contained feature-independent category markers. Well before language production starts, labels help infants to discover categories without relying on perceptual similarities across objects and build category representations with summary elements that may be critical for the development of abstract thought.
Detection of vanA genes in vancomycin susceptible E. faecium isolates; implications for additional testing
Authors: Jordan Victoria , Varadhan Hemalatha
Published: November 2024

To assess the frequency of silent vancomycin resistance, phenotypically susceptible E. faecium isolates underwent genotypic testing using Cepheid’s Xpert vanA/vanB PCR. 6% of isolates had silent vanA genes. However, the clinical relevance of silent van genes, and the lack of rapid, random-access genotypic methods poses an ongoing challenge to laboratories.
Predicting whole-brain neural dynamics from prefrontal cortex fNIRS signal during movie-watching
Authors: Gao Shan , Nash Ryleigh , Burns Shannon , Leong Yuan Chang
Published: November 2024

Functional near-infrared spectroscopy (fNIRS) offers a portable, cost-effective alternative to functional magnetic resonance imaging (fMRI) for non-invasively measuring neural activity. However, fNIRS measurements are limited to cortical regions near the scalp, missing important medial and deeper brain areas. We introduce a predictive model that maps prefrontal fNIRS signals to whole-brain fMRI activity during movie-watching. By aligning neural responses to a common audiovisual stimulus, our approach leverages shared dynamics across imaging modalities to map fNIRS signals to broader neural activity patterns. We scanned participants with fNIRS and utilized a publicly available fMRI dataset of participants watching the same TV episode. The model was trained on the first half of the episode and tested on a held-out participant watching the second half to assess cross-individual and cross-stimulus generalizability. The model significantly predicted fMRI time courses in 66 out of 122 brain regions, including in areas otherwise inaccessible to fNIRS. The predicted fMRI time course also replicated intersubject functional connectivity patterns and retained semantic information about the movie content. Our publicly available model enables researchers to infer broader neural dynamics from localized fNIRS data, offering new opportunities for studying the neural basis of complex cognitive processes during naturalistic tasks.
A simple new alternative to the linear-quadratic model (and where the LQ model comes from)
Authors: Bilinsky L. M.
Published: November 2024

I present a new dose-survival equation for fitting clonogenic assay data collected for irradiated cells, one motivated by the hypothesis that all cellular activities can be partitioned into two states (“state R” and “state Q”) which differ in their sensitivity to low-LET radiation. The LQ model can be derived from it by taking a Taylor expansion. The empirical observation that rapidly proliferating cancer cells have a straighter dose-survival relationship, while slowly proliferating cancer cells and normal cells have a curvier one featuring a shoulder region, is explained in terms of state R and state Q. The new equation (1) provides a convention for classifying cells as radioresistant, (2) provides a means of reducing, or possibly eliminating, cell cycle phase as a variable in treatment outcome, and (3) may enable standardization of the results reported for clonogenic assays. Finally, a novel hypothesis is offered for the “oxygen enhancement ratio” phenomenon.
Association of APOE gene polymorphisms and multiple risk factors with hypertension in middle-aged and elderly Tibetan population in Tibet on Bayesian network model
Authors: Zhang Yufei , Zhang Jing , Yao Yuan , Yan Jiaojiao , Chun Hua , Xiong Hai
Published: November 2024

BACKGROUND

The distribution of Apolipoprotein E (APOE) gene and its relationship with hypertension at high altitude in Tibet have not been elucidated. The purpose of this study was to understand the distribution of APOE genotypes and APOE rs7412, rs429358 genotypes in the middle-aged and elderly Tibetan population in Tibet, and to explore the related influencing factors by constructing a Bayesian network model of hypertension in middle-aged and elderly Tibetans.

METHODS

From November 2021 to November 2022, a multi-stage cluster random sampling method was employed to collect data from 511 middle-aged and elderly Tibetans residing in the Ali region, Nagqu City, and Shannan City of Tibet. The APOE gene, rs429358 and rs7412 single nucleotide polymorphisms (SNPs) were analyzed by fluorescence polymerase chain reaction (PCR). Multivariate logistic regression analysis and Bayesian Network (BN) were applied to examine the relationship between Covariates and hypertension.

RESULTS

Among all subjects, the frequencies of genotypes ε2/ε3, ε2/ε4, ε3/ε3 and ε3/ε4 were 14.8%,1.8%,75.0%, and 8.4%, respectively. APOE gene rs7412 locus CC, CT and TT genotype frequencies were 83.4%, 0 and 16.6%, respectively, and rs429358 locus TT, TC and CC genotypes, genotype frequencies were 89.8%, 10.2% and 0. The results of this study indicated no correlation between APOE genotypes, APOE rs7412, rs429358 genotypes, and the prevalence of hypertension in middle-aged and elderly Tibetan population in Tibet. Sex, age, overweight obesity, hyperhomocysteinemia (HHcy) and High Altitude Pulmonary Edema (HAPC) represent direct risk factors for hypertension based on a Bayesian network.

CONCLUSIONS

APOE genotype and APOE rs7412, rs429358 genotypes were not genetically correlated with hypertension in middle-aged and elderly Tibetan populations in Tibet. The Bayesian network model revealed the direct and indirect factors and the strength of the association of the hypertension. Additionally, it elucidated the complex network relationships among these factors, which provided a scientific basis for the early prevention of hypertension among middle-aged and elderly Tibetan populations in Tibet.
Optimizing Neoadjuvant Treatment Response Prediction for Triple-Negative Breast Cancer Using Clinical Trial Data and Deep Auxiliary Learning
Authors: Moon Chang In , Zhang Bing
Published: November 2024

Motivation

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. Developing predictive models for TNBC treatment responses is crucial but challenging due to data scarcity and the reliance on cell line data, which limits clinical translational value. Leveraging omics data from clinical trials, particularly through auxiliary learning, offers a potential solution to enhance predictive accuracy and reduce data requirements.

Results

In this study, we propose a new approach utilizing deep auxiliary task reweighting learning methods to automatically reweight auxiliary tasks, thereby optimizing the performance of the primary task of predicting TNBC treatment responses. We benchmark various auxiliary learning methods, including ARML, AdaLoss, GradNorm, and OL AUX, against traditional supervised machine learning algorithms and single-task learning baselines. Our results characterize the performance of auxiliary learning across various contexts, including utilizing parallel treatment arms within a multi-arm clinical trial, leveraging treatment arms from different clinical trials, and integrating multiple arms with the same treatment regimens across separate clinical trials. The last scenario also provides an opportunity for validating prediction models on an independent dataset, demonstrating the superior performance of the auxiliary learning models in predicting pathological complete response (pCR) in TNBC patients treated with standardized combinational chemotherapy with Taxane, Anthracycline, and Cyclophosphamide (TAC).

Availability and Implementation

Source code and additional resources can be accessed athttps://github.com/moonchangin/DeepAuxTxPred TNBC.
Unique pharmacology of mGlu homo- and heterodimers
Authors: McCullock Tyler W. , Couch Tyler , Kammermeier Paul J.
Published: November 2024

Background and Purpose

Metabotropic glutamate receptors (mGlus) are obligate dimer G protein coupled receptors that can all homodimerize and heterodimerize in select combinations. Responses of mGlu heterodimers to selective ligands, including orthosteric agonists and allosteric modulators, are largely unknown.

Experimental Approach

The pharmacological properties of each group II and III mGlu homodimer (except mGlu6) and several heterodimers were examined when stochastically assembled in HEK293T cells, or specifically measured using an improved G protein mediated BRET assay employing complimented fragments of NanoLuciferase.

Results

Stochastically assembled receptors adopted unique signaling characteristics. Some favored the potency, efficacy or signaling kinetics of a dominant subunit, while others exhibited blended profiles reflective of a combination of homo- and heterodimers at various ratios of expressed receptor. Finally, group II and III mGlu dimers were examined for responses to selective agonists and allosteric modulators. Effects of glutamate and selective group II and III orthosteric agonists were found to result in unique concentration response profiles when examining each combination of group II and II mGlu. Effects of select allosteric modulators were examined for each mGlu2 containing dimer as well as several group III dimer pairs. Likewise, allosteric modulator effects were often unique across dimers containing the targeted subunit of the ligand being tested.

Conclusions

Results demonstrate that mGlu dimers respond uniquely to selective ligands, and show that the mGlu family is not governed by generalizable rules dictating consequences of dimeric subunit interactions leading to signaling consequences.
The evolutionary path of the epithelial sodium channel δ-subunit in Cetartiodactyla points to a role in sodium sensing
Authors: Zahnow Fynn , Jäger Chiara , Mohamed Yassmin , Vogelhuber Gianluca , May Fabian , Ciocan Alexandra Maria , Manieri Arianna , Maxeiner Stephan , Krasteva-Christ Gabriela , Cobain Matthew R. D. , Podsiadlowski Lars , Crespo-Picazo José Luis , García-Párraga Daniel , Althaus Mike
Published: November 2024

The epithelial sodium channel (ENaC) plays a key role in osmoregulation in tetrapod vertebrates and is a candidate receptor for salt taste sensation. There are four ENaC subunits (α, β, γ, δ) which form αβγ- or δβγ ENaCs. While αβγ-ENaC is a ‘maintenance protein’ controlling sodium and potassium homeostasis, δβγ-ENaC might represent a ‘stress protein’ monitoring high sodium concentrations. The δ-subunit emerged with water-to-land transition of tetrapod vertebrate ancestors. We investigated the evolutionary path of ENaC-coding genes in Cetartiodactyla, a group comprising even-toed ungulates and the cetaceans (whales/dolphins) which transitioned from terrestrial to marine environments in the Eocene. The genesSCNN1A(α-ENaC),SCNN1B(β-ENaC) andSCNN1G(γ-ENaC) are intact in all 22 investigated cetartiodactylan families. WhileSCNN1D(δ-ENaC) is intact in terrestrial Artiodactyla, it is a pseudogene in 12 cetacean families. A fusion ofSCNN1Dexons 11 and 12 under preservation of the open reading frame was observed in the Antilopinae, representing a new feature of this clade. Transcripts ofSCNN1A,SCNN1BandSCNN1Gwere present in kidney and lung tissues of Bottlenose dolphins, highlighting αβγ-ENaC’s role as a maintenance protein. Consistent withSCNN1Dloss, Bottlenose dolphins and Beluga whales did not show behavioural differences to stimuli with or without sodium in seawater-equivalent concentrations. These data suggest a function of δ-ENaC as a sodium sensing protein which might have become obsolete in cetaceans after the migration to high-salinity marine environments. Consistently, there is reduced selection pressure or pseudogenisation ofSCNN1Din other marine mammals, including sirenians, pinnipeds and sea otter.
Spatio-temporal T cell tracking for personalized TCR-T designs in childhood cancer
Authors: Sentís Inés , Melero Juan L. , Cebria-Xart Alex , Grzelak Marta , Soto Marta , Michel Alexandra , Rovira Quirze , Rodriguez-Hernandez Carlos J. , Caratù Ginevra , Urpi-Badell Andrea , Sauvage Christophe , Mendizabal-Sasieta Ana , Maspero Davide , Pascual-Reguant Anna , Muñoz Perez Juan Pablo , Mora Jaume , Harari Alexandre , Nieto Juan C. , Avgustinova Alexandra , Heyn Holger
Published: November 2024

Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers. Here, we present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized TCR-T cell therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood. Specifically, we tracked T cell dynamics longitudinally from the tumor to cells in circulating over a time course of 12 months, revealing a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T cell dynamics in the blood post-ICI to predict tumor-reactivity. These findings strongly support spatio-temporal tracking of T cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.
Preclinical Evaluation of PTK7-Targeted Radionuclide Therapy
Authors: Lindland Kim , Westrøm Sara , Dragovic Srdan M. , Li Ruth Gong , Malenge Marion Masitsa , Ho Betty , Juzeniene Asta , Bønsdorff Tina Bjørnlund
Published: November 2024

Protein tyrosine kinase 7 (PTK7), a receptor found in tumor-initiating cells, is expressed in various malignancies, including ovarian cancer. While PTK7 has been explored as a target for antibody-drug conjugates, this study is the first to investigate its potential for targeted radionuclide therapy. We developed a murine monoclonal IgG1 antibody (mOI-1) using hybridoma technology and generated a chimeric version (chOI-1) with human IgG1 constant regions. A cell-based screening approach using a library of 6100 cell surface proteins identified PTK7 as the target, confirmed by flow cytometry and surface plasmon resonance analyses. Immunohistochemistry showed strong PTK7 expression in ovarian cancer tissues, andin vitrostudies demonstrated specific binding and internalization of OI-1 in the ovarian cancer cell line SKOV-3-luc. Biodistribution studies using177Lu-DOTA-mOI-1 injected intravenously in xenograft mice with subcutaneous SKOV-3-luc revealed high tumor uptake and retention. Therapeutic efficacy was assessed by intraperitoneal treatment with212Pb-TCMC-chOI-1 in an intraperitoneal xenograft model, showing significant tumor growth inhibition compared to non-radioactive controls. This study provides the first proof-of-principle for using the PTK7-targeting OI-1 antibody as an antibody-radionuclide conjugate (212Pb-labeled), demonstrating its therapeutic potential in a preclinical model of intraperitoneal ovarian cancer. These results support further investigation of OI-1 as a candidate for targeted radionuclide therapy in PTK7-expressing cancers.
Innovative mutant screening identifiesTRANSPARENT TESTA7as a player in seed oil/protein partitioning
Authors: Lécureuil Alain , Corso Massimiliano , Boutet Stéphanie , Gall Sophie Le , Niñoles Regina , Gadea Jose , Guerche Philippe , Jasinski Sophie
Published: November 2024

Brassicaceae species mainly accumulate oil and protein in their seeds, which are essential to human life as a source of food, but also as animal feed and resources for green chemistry. To date, Brassicaceae crops such as rapeseed have been selected mainly for their oil content. However, there is a growing interest in their seed protein content. A strong negative correlation between oil and protein content makes it difficult to increase both compounds simultaneously. In this study, anArabidopsis thalianahomozygous EMS mutant library was screened by near-infrared spectroscopy for seed oil and protein content, with the aim of identifying mutants with impaired oil-protein correlation. The mutant most affected in this correlation was found to be in theTRANSPARENT TESTA7gene, which is involved in the flavonoid biosynthetic pathway. Analysis of different mutants in the flavonoid pathway revealed that thett7mutants were the only ones to show such a significant reduction in seed oil content, highlighting a phenotype never described before for thett7mutants and suggesting a specific role for TT7 in the interplay between the oil and flavonoid biosynthetic pathways. Untargeted metabolomic analysis allowed the identification of metabolic features that are highly accumulated and specific tott7seeds compared to the other genotypes and genetic analysis established that the accumulation of kaempferol-3-O-rhamnoside seems to be responsible for the seed oil reduction oftt7mutants.

Significance Statement

Brassicaceae species accumulate oil and protein in their seeds and understanding how the partitioning of these compounds is regulated is necessary to engineer seeds for specific purposes. By screening an Arabidopsis EMS mutant library, we identified mutants affected in seed oil/protein partitioning, includingtt7, highlighting a link between oil and flavonoid biosynthetic pathways, that we explore further in this paper.
Spatially Resolvedin vivoCRISPR Screen Sequencing via Perturb-DBiT
Authors: Baysoy Alev , Tian Xiaolong , Zhang Feifei , Renauer Paul , Bai Zhiliang , Shi Hao , Li Haikuo , Tao Bo , Yang Mingyu , Enninful Archibald , Gao Fu , Wang Guangchuan , Zhang Wanqiu , Tran Thao , Patterson Nathan Heath , Bao Shuozhen , Dong Chuanpeng , Xin Shan , Zhong Mei , Rankin Sherri , Guy Cliff , Wang Yan , Connelly Jon P. , Pruett-Miller Shondra M. , Chi Hongbo , Chen Sidi , Fan Rong
Published: November 2024

Perturb-seq enabled the profiling of transcriptional effects of genetic perturbations in single cells but lacks the ability to examine the impact on tissue environments. We present Perturb-DBiT for simultaneous co- sequencing of spatial transcriptome and guide RNAs (gRNAs) on the same tissue section for in vivo CRISPR screen with genome-scale gRNA libraries, offering a comprehensive understanding of how genetic modifications affect cellular behavior and tissue architecture. This platform supports a variety of delivery vectors, gRNA library sizes, and tissue preparations, along with two distinct gRNA capture methods, making it adaptable to a wide range of experimental setups. In applying Perturb-DBiT, we conducted un-biased knockouts of tens of genes or at genome-wide scale across three cancer models. We mapped all gRNAs in individual colonies and corresponding transcriptomes in a human cancer metastatic colonization model, revealing clonal dynamics and cooperation. We also examined the effect of genetic perturbation on the tumor immune microenvironment in an immune-competent syngeneic model, uncovering differential and synergistic perturbations in promoting immune infiltration or suppression in tumors. Perturb-DBiT allows for simultaneously evaluating the impact of each knockout on tumor initiation, development, metastasis, histopathology, and immune landscape. Ultimately, it not only broadens the scope of genetic inquiry, but also lays the groundwork for developing targeted therapeutic strategies.
Single cell analysis of Barrett’s esophagus and carcinoma reveals cell types conferring risk via genetic predisposition
Authors: Wenzel Marten C. , Giel Ann-Sophie , Plum Patrick S. , Hoppe Sascha , Franitza Marek , Jonas Christoph , Dasmeh Pouria , Thieme René , Zhao Yue , Heider Dominik , Palles Claire , Fitzgerald Rebecca Claire , Bruns Christiane J. , Buettner Reinhard , Quaas Alexander , Gockel Ines , Maj Carlo , Chon Seung-Hun , Schumacher Johannes , Hillmer Axel M.
Published: November 2024

Inherited genetic variants contribute to Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) but it is unknown which cell types are involved in this process. We performed single cell RNA-sequencing of BE, EAC and paired normal tissues and integrated data of a genome-wide association study to determine cell type-specific genetic risk and cellular processes that contribute to BE and EAC. The analysis revealed that EAC development is driven to a greater extent by local cellular processes than BE development. One cell type of BE origin (BE-EAC) and cellular processes that control the differentiation of columnar cells are of particular relevance for EAC development. Further, specific subtypes of fibroblasts and endothelial cells contribute to BE and EAC development, while dendritic cells and CD4+ memory T cells contribute exclusively to BE development. The diagnostic use of markers characterizing the identified cell types and cellular processes should be explored in future for EAC prediction.