bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients’ Experiences of Dental Diagnostic Failures: A Qualitative Study Using Social Media
Authors: Obadan-Udoh Enihomo , Howard Rachel , Valmadrid Luke Carmichael , Walji Muhammad , Mertz Elizabeth
Published: February 2024

Objective

Despite the many advancements made in patient safety over the past decade, combating diagnostic errors (DEs) remains a crucial, yet understudied initiative toward improvement. This study sought to understand the perception of dental patients who have experienced a dental diagnostic failure (DDF) and to identify patient-centered strategies to help reduce future occurrences of DDF.

Methods

Through social media recruitment, we conducted a screening survey, initial assessment, and 67 individual patient interviews to capture the effects of misdiagnosis, missed diagnosis, or delayed diagnosis on patient lives. Audio recordings of patient interviews were transcribed, and a hybrid thematic analysis approach was used to capture details about 4 main domains of interest: the patient’s DDF experience, contributing factors, impact, and strategies to mitigate future occurrences.

Results

Dental patients endured prolonged suffering, disease progression, unnecessary treatments, and the development of new symptoms as a result of experiencing DE. Poor provider communication, inadequate time with provider, and lack of patient self-advocacy and health literacy were among the top attributes patients believed contributed to the development of a DE. Patients suggested that improvements in provider chairside manners, more detailed patient diagnostic workups, and improving personal self-advocacy; along with enhanced reporting systems, could help mitigate future DE.

Conclusions

This study demonstrates the valuable insight the patient perspective provides in understanding DEs, therefore aiding the development of strategies to help reduce the occurrences of future DDF events. Given the challenges patients expressed, there is a significant need to create an accessible reporting system that fosters constructive clinician learning.
Low-Grade Papillary Schneiderian Carcinoma in the Nasal Cavity
Authors: Im Yeon Hee , Choi Dahae , Nam Inn-Chul
Published: February 2024

Only a limited number of documented low-grade papillary Schneiderian carcinoma (LGPSC) cases have been reported since its initial description in 2015. In this study, the authors present a case report involving a young female patient who presented with this rare condition localized in the nasal cavity. On the basis of histologic examination of a small tumor sample, the initial diagnosis pointed to squamous cell carcinoma. After the surgery, however, the final histologic diagnosis was confirmed as LGPSC. Finally, after surgical intervention, the histologic diagnosis was confirmed as LGPSC. Remarkably, over a period of 22 months, the patient showed no signs of recurrence or metastasis. To achieve an accurate diagnosis and implement appropriate treatment strategies for LGPSC, a comprehensive understanding of both its clinical and histologic characteristics is necessary.
A Systematic Review of Technique, Satisfaction, and Complications of Acellular Dermal Matrix in Rhinoplasty
Authors: Tang Yongsheng , Han Xuan , Li Jiaxin , Cao Yi , Gong Yanxi , Xu Chao
Published: February 2024

Objective:

Acellular dermal matrix (ADM) is a new dermal transplant replacement material prepared from allogeneic or xenograft skin through bioengineering technology. This is provided for patients who are unwilling to kill part of their autologous cartilage or autologous dermal tissue and require rhinoplasty and improvement in the appearance of the nasal tip. This systematic review aims to introduce the main techniques of ADM for rhinoplasty and related patient satisfaction and complications to further guide doctors.

Methods:

Systematic reviews were conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The authors searched PubMed, Web of Science, Embase, and Cochrane Library using appropriate keywords. Data collected for each study included patient satisfaction and complications in addition to relevant technology.

Results:

After full-text screening of inclusion and exclusion criteria, 10 studies were included, with a total of 324 patients receiving ADM with different transplantation methods. Primary rhinoplasty or secondary rhinoplasty study for dorsal ridge augmentation, smooth contour irregularities, autograft camouflage including tip grafts. The incidence of dorsal implant distortion was 0.72% in patients. The incidence of deviation was 2.17% in patients. The incidence of mild edema was 5.17% in patients. The incidence of partial resorption was 10.87% in patients. The incidence of significant resorption was 13.04% in patients. The incidence of seroma was 0.72% in patients. The incidence of partial prolapse was 0.72% in patients. The incidence of overcorrection and reoperation was 0.72% in patients. The incidence of erythema was 0.72% in patients. The incidence of undercorrection was 0.72% in patients. The incidence of infection was 0.72% in patients. The incidence of high-lying implants was 1.45% in patients.

Conclusion:

The current research results show that ADM is long-term effective in improving nasal dorsum enhancement, nasal contour deformity, and nasal tip appearance, with high patient satisfaction and low overall complication rate. Overcorrection should be considered during surgery to deal with postoperative partial absorption.
Genetics and Epigenetics in the Genesis and Development of Microtia
Authors: Chen Xin , Ma Jing , Zhang Tianyu
Published: February 2024

Microtia is a congenital malformation of the external and middle ear associated with varying degrees of severity that range from mild structural abnormalities to the absence of the external ear and auditory canal. Globally, it is the second most common congenital craniofacial malformation and is typically caused by inherited defects, external factors, or the interaction between genes and external factors. Epigenetics notably represents a bridge between genetics and the environment. This review has devoted attention to the current proceedings of the genetics and epigenetics of microtia and related syndromes.
Recent advances in bronchoscopic lung volume reduction for severe COPD patients
Authors: Posthuma Rein , Vaes Anouk W. , Spruit Martijn A. , Vanfleteren Lowie E.G.W.
Published: February 2024

Purpose of review

Bronchoscopic lung volume reduction (BLVR) is a novel and effective treatment for a specific phenotype of chronic obstructive pulmonary disease (COPD) characterized by advanced emphysema with static lung hyperinflation and severe breathlessness. This review aims to provide an overview of the recent advances made in BLVR.

Recent findings

For achieving optimal outcomes with BLVR, patient selection and target lobe identification is crucial. BLVR has recently also been established to improve pulmonary function, exercise capacity and quality of life in COPD patients falling outside the standard treatment criteria, including patients with moderate hyperinflation, chronic hypercapnic failure or with very low diffusion capacity. In a cluster analysis, target lobe characteristics like emphysema destruction, air trapping and perfusion were found to be important discriminators between responders and non-responders. A potential survival benefit has been demonstrated in BLVR-treated patients when compared to non-treated patients. Long-term outcomes showed sustained outcomes of BLVR; however, effects decline over time, probably due to disease progression.

BLVR using one-way endobronchial valves has become a guideline treatment offered in specialized intervention centres for a specific subgroup of COPD patients. Recent studies further characterize responders, describe extrapulmonary effects of BLVR and show positive long-term outcomes and a potential survival benefit.
Reduction of Urinary Tract Infection in Pediatric Surgical Patients Using NSQIP-P and Quality Improvement Methodology
Authors: Clasie Kyla A , Deshpande Aniruddh V , Holland Andrew JA , Jiwane Ashish V , Da Silva Vanessa G , Filtness Fiona A , Allen Margaret M , Smith Grahame HH
Published: February 2024

BACKGROUND:

Hospital-acquired urinary tract infections (UTIs) have a detrimental effect on patients, families, and hospital resources. The Sydney Children’s Hospital Network (SCHN) participates in the NSQIP-Pediatric (NSQIP-P) to monitor postoperative complications. NSQIP-P data revealed that the median UTI rate at SCHN was 1.75% in 2019, 3.5 times higher than the NSQIP-P target rate of 0.5%. Over three quarters of the NSQIP-P identified patients with UTI also had a urinary catheterization performed intraoperatively. A quality improvement project was conducted between mid-2018 and 2021 to minimize catheter-associated UTIs (CAUTIs) at SCHN.

STUDY DESIGN:

NSQIP-P samples include pediatric (younger than 18 years) surgical patients from an 8-day cycle operative log. NSQIP-P data are statistically analyzed by the American College of Surgeons and provide biannual internationally benchmarked reports. The project used clinical redesign methodology with a 6-phase process for quality improvement projects.

RESULTS:

The objectives of the project were to reduce urinary catheter duration of use, educate parents or carers, and improve catheter care and insertion technique by health staff. The duration of a urinary catheter in situ reduced from a median of 4.5 to 3 days from 2017 to 2021. The median NSQIP-P UTI rate at SCHN was reduced by 47.4% from 1.75% in 2019 to 0.9% in 2022.

CONCLUSIONS:

A multifactorial approach in quality improvement has been shown to be an effective strategy to reduce UTI rates at SCHN, and patient outcomes were improved within a 3-year timeframe. Although this project has reduced UTI rates at SCHN, there remain opportunities for further improvement.
Multiple interspecies recombination events documented by whole-genome sequencing in multidrug-resistant Haemophilus influenzae clinical isolates
Authors: Michel Charlotte , Argudín Maria De Los Angeles , Wautier Magali , Echahidi Fedoua , Prevost Benoit , Vandenberg Olivier , Martiny Delphine , Hallin Marie
Published: February 2024

Introduction.

Haemophilus influenzae

(Hi) was long known as an easy-to-treat bacterium, but increasing resistance against beta-lactams and other critically important antibiotics is now a growing concern. We describe here the whole-genome sequencing (WGS) analysis of three non-typeable Hi isolates received in 2018–2019 by the Belgian National Reference Centre (NRC) for

Haemophilus influenzae

, as they presented an unusual multi-resistant profile.

Methods. All three isolates were sequenced by WGS and mapped to the reference isolate Hi Rd KW20. Shorten uptake signal sequences (USSs) known to be associated with homologous recombination were sought in ftsI, murE and murF genes, and inner partial sequences were compared against the blast nucleotide database to look for similarity with other

Haemophilus

species. Their antimicrobial resistance (AMR) genotype was studied. Core-genome multilocus sequence typing (MLST) was performed on the NTHi database pubMLST to place our isolates in the actual worldwide epidemiology.

Results. The isolates also harboured interspecies recombination patterns in the murF-murE-ftsI region involved in cell wall synthesis. The three isolates were multidrug resistant and two of them were also resistant to amoxicillin–clavulanic acid and showed a reduced susceptibility to meropenem. All three isolates belonged to the MLST clonal complex (CC) 422, and WGS revealed that the three were very similar. They harboured mobile genetic elements (carrying blaTEM-1B, mefA and msrD genes associated with resistance), mutations in gyrA and parC linked to fluoroquinolone resistance as well as remodelling events in ompP2 that might be related to lower carbapenem susceptibility.

Conclusion. The Hi evolution towards antimicrobial multiresistance (AMR) is a complex and poorly understood phenomenon, although probably linked to a large degree to the presence of USSs and exchange within the family

Pasteurellaceae

. To better understand the respective roles of clonal expansion, horizontal gene transfers, spontaneous mutations and interspecies genetic rearrangements in shaping Hi AMR, both analysis of Hi communities over time within individuals and worldwide monitoring of non-typeable Hi causing infections should be conducted.
Rational Design of Monomeric IL37 Variants Guided by Stability and Dynamical Analyses of IL37 Dimers
Authors: Sardag Inci , Duvenci Zeynep Sevval , Belkaya Serkan , Timucin Emel
Published: February 2024

IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response triggered by IL18 through binding to the IL18 receptorα, a capability lost in its dimeric form. This paradigm underscores the pivotal role of IL37’s dimer structure in the design of novel anti-inflammatory therapeutics. Hitherto, two IL37 dimer structures were deposited in PDB, reflecting the potential use of their binding interface in the design of IL37 variants with altered dimerization tendencies. Inspection of these static structures suggested a substantial difference in their dimer interfaces. Prompted by this discrepancy, we analyzed the PDB structures of IL37 dimer (PDB: 6ncu and 5hn1) along with a predicted structure by AF2-multimer by molecular dynamics (MD) simulations to unravel whether and how IL37 can form homodimers through distinct interfaces. Results showed that the 5hn1 and AF2 dimers, which shared the same interface, stably maintained their initial conformations throughout the simulations whilst the recent IL37 dimer (PDB ID: 6ncu) with a different interface, did not. These findings underscored that the recent IL37 dimer (6ncu) structure is likely to contain an error, probably in its biological assembly record, otherwise it was not a stable assemblyin silico. Next, focusing on the stable dimer structure of 5hn1, we have identified five critical positions of V71/Y85/I86/E89/S114 that would altogether reduce dimer stability without affecting the monomer fold. Two quintet mutations were tested similarly by MD simulations and both mutations showed either partial or complete dissociation of the dimeric form. Overall, this work contributes to the development of IL37-based therapeutics by accurately representing the dimer interface in the PDB structures and identifying five potential substitutions to effectively inhibit the inflammatory response triggered by IL18.
A Multiscale Sensorimotor Model of Experience-Dependent Behavior in a Minimal Organism
Authors: Vidal-Saez María Sol , Vilarroya Oscar , Garcia-Ojalvo Jordi
Published: February 2024

To survive in ever-changing environments, living organisms need to continuously combine the ongoing external inputs they receive, representing present conditions, with their dynamical internal state, which includes influences of past experiences. It is still unclear in general, however, (i) how this happens at the molecular and cellular levels, and (ii) how the corresponding molecular and cellular processes are integrated with the behavioral responses of the organism. Here we address these issues by modeling mathematically a particular behavioral paradigm in a minimal model organism, namely chemotaxis in the nematodeC. elegans. Specifically, we use a long-standing collection of elegant experiments on salt chemotaxis in this animal, in which the migration direction varies depending on its previous experience. Our model integrates the molecular, cellular and organismal levels to reproduce the experimentally observed experience-dependent behavior. The model proposes specific molecular mechanisms for the encoding of current conditions and past experiences in key neurons associated with this response, predicting the behavior of various mutants associated with those molecular circuits.
Tests for Segregation Distortion in Tetraploid F1 Populations
Authors: Gerard David , Thakkar Mira , Ferrão Luis Felipe V.
Published: February 2024

Genotype data from tetraploid F1 populations are often collected in breeding programs for mapping and genomic selection purposes. A common quality control procedure in these groups is to compare empirical genotype frequencies against those predicted by Mendelian segregation, where SNPs detected to have “segregation distortion” are discarded. However, current tests for segregation distortion are insufficient in that they do not account for double reduction and preferential pairing, two meiotic processes in polyploids that naturally change gamete frequencies, leading these tests to detect segregation distortion too often. Current tests also do not account for genotype uncertainty, again leading these tests to detect segregation distortion too often. Here, we incorporate double reduction, preferential pairing, and genotype uncertainty in likelihood ratio and Bayesian tests for segregation distortion. Our methods are implemented in a user-friendly R package, menbayes. We demonstrate the superiority of our methods to those currently used in the literature on both simulations and real data.
Intrauterine Growth-Restricted Pregnant Rats, from Hypertensive Placental Ischemic Dams Display Preeclamptic-like Symptoms: A New Rodent Model of Preeclampsia
Authors: Smith Jonna , Powell Madison , Cromartie Whitney , Smith Savanna , Jones Kylie , Castillo Angie , Shaw Jordan , Editone Joseph , Howard-Cunningham Ahfiya , Tatum Robert , Smith Alex , Fisher Brandon , Booz George W. , Cunningham Mark
Published: February 2024

Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is one of the primary causes of intrauterine growth restriction (IUGR). PE is associated with placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage.

Methods

Pregnant Sprague Dawley rats are divided into 2 groups: normal pregnant (NP) and reduced uterine perfusion pressure (RUPP) hypertensive placental ischemic dams. Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg; n=3-8) and pregnant CON (CON Preg; n=3-6) rats. BP and other markers of PE were evaluated during late gestation.

Results

Pregnant IUGR rats had elevated BP and systemic OS, as demonstrated by higher trending 8-isoprostanes and lower circulating antioxidant capacity. Maternal body weight of pregnant IUGR rats and their pups’ weights were decreased, while the brains were enlarged. Brain OS was elevated, with a rise in hydrogen peroxide (H2O2) and heat shock protein 1 (HSP- 1), along with lower Manganese Superoxide Dismutase (MnSOD) and antioxidant capacity.

Conclusion

Pregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Pregnant IUGR rats exhibit an preeclamptic-like phenotype, which suggests a new epigenetic model of PE.
Unveiling Circulating Targets in Pancreatic Cancer: Insights from Proteogenomic Evidence and Clinical Cohorts
Authors: Feng Haokang , Chen Zhixue , Li Jianang , Feng Jiale , Yang Fei , Meng Fansheng , Yin Hanlin , Guo Yuquan , Xu Huaxiang , Liu Yuxin , Liu Runjie , Lou Wenhui , Liu Liang , Han Xu , Su Hua , Zhang Lei
Published: February 2024

Pancreatic cancer (PC), lacking biomarkers and effective therapeutics, remains highly lethal. Data regarding the correlations of PC risk and the individual plasma proteome known for minimally cancer biomarkers, are scarce. Here, we measure 1,345 human plasma proteins via Proteome-Wide Association Studies, presenting 78 proteins are prominently related to PC risk, including 4 proteins (ROR1, FN1, APOA5, ABO) exhibit the strongest causal association identified via Mendelian Randomization and Colocalization. Our two independent cohorts further demonstrate FN1 and ABO are highly expressed in blood or tumors from patients with PC compared to specimens from healthy individuals or para-tumors. Moreover, patients with higher levels of FN1 and ABO in their blood or tumors have worse median survival than those with lower levels. Multiple drugs targeting FN1 are currently available or undergoing clinical testing, making FN1 a promisingly repurposed therapeutic target in addition to severing as a circulating prognostic indicator for PC.
RSV and Rhinovirus asymptomatic upper airway infection increases pneumococcal carriage acquisition rates and density in adults whereas nasal inflammation is associated with bacterial shedding
Authors: Mitsi Elena , Nikolaou Elissavet , Goncalves Andre , Blizard Annie , Hill Helen , Farrar Madlen , Hyder-Wright Angela , Howard Ashleigh , Elterish Filora , Solorzano Carla , Robinson Ryan , Reine Jesus , Collins Andrea M. , Gordon Stephen B. , Weiser Jeffrey N. , Bogaert Debby , Ferreira Daniela M.
Published: February 2024

Nasopharyngeal pneumococcal colonisation is a necessary step for disease development and the primary reservoir of bacterial spread and transmission. Most epidemiological studies report the impact of co-infection with respiratory viruses upon disease rates and outcome, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we used controlled human infection with pneumococcus to assess whether certain respiratory viruses alter susceptibility to pneumococcal colonisation and bacterial density. A total of 581 healthy adults were screened for presence of upper respiratory tract viral infection before intranasal pneumococcal challenge. We showed that RSV and Rhinovirus asymptomatic infection conferred a substantial increase in carriage rates (88% and 66% of colonised individuals in Rhinovirus and RSV infected groups, respectively, vs 49% in the virus negative group). The risk ratio of pneumococcal colonization in RSV infected group was 5.3 (95% CI: 0.90 – 30.61, p = 0.034) and 2.03 (95% CI: 1.09-3.80, p= 0.035) in rhinovirus infected group. Pneumococcal density was overall greater in virus positive subjects, although RSV infection alone had a major impact on pneumococcal density up to 9 days post challenge, with a substantial 2- log increase at D2 compared to virus negative group (median, SEM: 3.76 ± 0.65 vs 1.79 ± 0.09) (p= 0.02). We also studied rates and kinetics of bacterial shedding through the nose and oral route in a subset of challenged individuals. Nasal bacterial shedding was twice more frequent than cough-induced shedding (64% vs 32%, respectively). High levels of bacterial colonisation density and nasal inflammation was strongly correlated with increased odds of nasal shedding, as opposed to cough-shedding.

Healthy adults can act as reservoir of transmission for pneumococcus, particularly when colonised with high density and have local inflammation, two key characteristics of pneumococcal colonisation in paediatrics and/or viral co-infection. Hence, vaccines targeting these respiratory pathogens have the dual potential of reducing transmission and disease burden due to their indirect benefit to off target pathogens.
Restricting CAR T Cell Trafficking Expands Targetable Antigen Space
Authors: Morales Erin A. , Dietze Kenneth A. , Baker Jillian M. , Wang Alexander , Avila Stephanie V. , Iglesias Fiorella , Radhakrishnan Sabarinath V. , Mause Erica Vander , Olson Michael L. , Sun Wenxiang , Rosati Ethan , Chidester Sadie L. , Iraguha Thierry , Fan Xiaoxuan , Atanackovic Djordje , Luetkens Tim
Published: February 2024

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin ⍺4(A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4koLINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.

One sentence summary

Altering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity.

GRAPHICAL ABSTRACT
Binding Position Dependent Modulation of Smoothened Activity by Cyclopamine
Authors: Kim Kihong , Bansal Prateek D. , Shukla Diwakar
Published: February 2024

Cyclopamine is a natural alkaloid that is known to act as an agonist when it binds to the Cysteine Rich Domain (CRD) of the Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each binding site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Additionally, there is a possibility that cyclopamine could bind to both sites simultaneously especially at high concentration, the implications of which remain unknown. We performed three independent sets of simulations to observe the receptor activation with cyclopamine bound to each site independently (CRD, TMD) and bound to both sites simultaneously. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explored the dynamic behavior of cyclopamine’s interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower activation free energy barrier of∼2 kcal/mol, and expansion of the hydrophobic tunnel to facilitate cholesterol transport agrees with the cyclopamine’s agonistic behavior when bound to the CRD of SMO. A higher population of the inactive state at equilibrium, a higher free energy barrier of∼4 kcal/mol and restricted the hydrophobic tunnel to impede cholesterol transport showed cyclopamine’s antagonistic behavior when bound to TMD. With cyclopamine bound to both sites, there was a slightly larger inactive population at equilibrium and an increased free energy barrier (∼3.5 kcal/mol). The tunnel was slightly larger than when solely bound to TMD, and showed a balance between agonism and antagonism with respect to residue movements exhibiting an overall weak antagonistic effect.
Molecular attributes of the tropical treeAvicennia schauerianainvolved in the response and tolerance to low temperatures
Authors: de Moura Yohans Alves , Aono Alexandre Hild , Cruz Mariana Vargas , Pereira Alessandro Alves , Vidal João de Deus , de Souza Anete Pereira
Published: February 2024

Mangroves are coastal ecosystems of great socioenvironmental importance that are highly threatened by human activities. Mangrove trees live under harsh environmental conditions, which makes them sensitive to extreme weather events, particularly freezing events. Such events are unpredictable and have catastrophic consequences for mangrove trees; therefore, understanding and anticipating the impacts of such events are essential for directing future mitigation measures. Freezing cold currently limits the distribution of mangroves to tropical and subtropical latitudes worldwide. Mangrove trees are seriously affected by freezing conditions and suffer severe metabolic fluctuations due to photosystem and cellular structure damage. However, land plants more broadly have developed sophisticated mechanisms of resistance to freezing during their evolution, and the central molecular mechanisms involved in this process are consistent. However, the known information is restricted to models of herbaceous plants, such asArabidopsis thaliana, that are native to temperate habitats, and there is a research gap regarding tropical trees such as mangroves. This work aimed to improve the understanding of the molecular aspects of the response and tolerance to freezing in mangrove trees usingAvicennia schauerianaas a model. This species occurs within the colder range limits of South American mangroves and shows evidence of the existence of two functional groups that are locally adapted to the equatorial (EQ) and subtropical (ST) portions of the Brazilian coast. We investigated the transcriptional profiles of seedlings from both functional groups under freezing shock (−4°C) in a time series. We analyzed transcriptomic data by combining differential expression, coexpression network and protein interaction data. Our results allowed us to describe the profile of the molecular response ofA. schauerianato freezing and the divergence in the behavior of the EQ and ST functional groups. In EQ plants, the response strongly depended on the action of abscisic acid (ABA) and stress signals throughout the experiment. Notably, ABA negatively affects plant growth and promotes the accumulation of carotenoids, anthocyanins and lipids through chlorophyll degradation. On the other hand, in the ST, there were fewer hormones active in the process of primary growth maintenance and metabolic normalization. The accumulation of substances is mainly based on sucrose, anthocyanin and lipid levels, and lipid synthesis is not dependent on chlorophyll degradation. Based on these results, we hypothesize that susceptibility to freezing damage is greater in EQ mangroves than in ST mangroves. Therefore, we recommend that this fact be considered when managing this species, especially at higher latitudes, which are more prone to lower temperatures and extreme freezing events.
Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction
Authors: Pla Indira , Szabolcs Botond L. , Péter Petra Nikolett , Ujfaludi Zsuzsanna , Kim Yonghyo , Horvatovich Peter , Sanchez Aniel , Pawlowski Krzysztof , Wieslander Elisabet , Guedes Jéssica , Pál Dorottya MP , Ascsillán Anna A. , Betancourt Lazaro Hiram , Németh István Balázs , Gil Jeovanis , Almeida Natália Pinto de , Szeitz Beáta , Szadai Leticia , Doma Viktória , Woldmar Nicole , Bartha Áron , Pahi Zoltan , Pankotai Tibor , Győrffy Balázs , Szasz A. Marcell , Domont Gilberto , Nogueira Fábio , Kwon Ho Jeong , Appelqvist Roger , Kárpáti Sarolta , Fenyö David , Malm Johan , Marko-Varga György , Kemény Lajos V.
Published: February 2024

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes.

By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype.

We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.

Highlights

(1)

Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma

(2)

Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients

(3)

20 compounds identified that show potential effectiveness in at least one melanoma subtype

(4)

Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes

Graphical abstract
Therapeutic potential of glabridin and gymnemic acid alleviates eye choroidal thickness and neovascularization in diabetic model rats
Authors: Komolkriengkrai Manaras , Matsathit Udomlak , Khimmaktong Wipapan
Published: February 2024

Small blood vessels in the eyes are more susceptible to injury, which can lead to complications. However, since diabetic retinopathy is often a serious clinical condition, most of this study focuses on the vascular system of the choroid. As part of this study, we looked at how gymnemic acid (fromGymnema sylvestre) and glabridin (fromGlycyrrhiza glabra, or licorice) might help diabetic rats’ choroid thickness and blood vessels. The aim of this study was to explore the effects of glabridin and gymnemic acid on the structural changes of the choroidal layer as well as the expression of VEGF and CD31 in diabetic rats. The animals were separated into five groups: the control group (Control), the diabetic group (DM), the diabetic rats treated with glabridin 40 mg/kg body weight (DM+GB), the diabetic rats treated with gymnemic acid 400 mg/kg body weight (DM+GM), and the diabetic rats treated with glyburide 4 mg/kg body weight (DM+GR). There was an increase in the thickness of both the choroid layer and the wall of the arteries in the diabetic group. A decrease in vascularity and choroidal neovascularization was found in DM rats. After eight weeks of experimentation, the choroidal thickness increased and the walls of choroid arteries, as well as the diameter of the lumen of choroid arteries in the DM+GB, DM+GM, and DM+GR groups, were wider. The expression of VEGF and CD31 was lower compared to the DM group. According to the findings of the current research, glabridin and gymnemic acid can reduce the damage to the choroid, which is a factor that can sometimes result in vision loss.
Comparative analysis of Formyl peptide receptor 1 and Formyl peptide receptor 2 reveals shared and preserved signaling profiles
Authors: Pajonczyk Denise , Sternschulte Merle F. , Soehnlein Oliver , Bermudez Marcel , Raabe Carsten A. , Rescher Ursula
Published: February 2024

Pattern Recognition Receptors are key in identifying pathogenic or damaged cell-related patterns or molecules. Among these, the closely linked formyl peptide receptors FPR1 and FPR2 are believed to hold pivotal yet differing functions in immune regulation. To address the intriguing question of how these highly related receptors with a shared agonist spectrum play differing roles in modulating inflammation, we analyzed the signaling profile for a panel of FPR agonistsin vivoandex vivosettings. Our analysis uncovered a shared core signature for both FPRs across signaling pathways. Whereas formylated peptides generally acted as potent agonists at FPR1, FPR2 agonists, irrespective of N-terminal formylation, displayed consistently low activity ratios, suggesting an underutilized signaling potential of this receptor. Signaling outcomes were defined by specific agonist-receptor pairings and no receptor-specific signaling texture was identified. Activation of the FPR signaling axis by fMLF in human neutrophils did impact neutrophil survival. Overall, the distinct characteristics underlying inflammatory, anti-inflammatory, or pro-resolving profiles could not be attributed to a specific receptor isoform, signaling pattern, or a particular class of agonists, challenging assumptions about distinct inflammatory profiles linked to specific receptors, signaling patterns, or agonist classes.
NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation
Authors: Forsyth Katherine S. , Toothacre Natalie E. , Jiwrajka Nikhil , Driscoll Amanda M. , Shallberg Lindsey A. , Cunningham-Rundles Charlotte , Barmettler Sara , Farmer Joceyln , Verbsky James , Routes John , Beiting Daniel P. , Romberg Neil , May Michael J. , Anguera Montserrat C.
Published: February 2024

X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment ofXistRNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of TCR, is required. Disruption of NF-κB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-κB signaling pathways which impact XCI maintenance in female T cells.
Semi-supervised Bayesian integration of multiple spatial proteomics datasets
Authors: Coleman Stephen D. , Breckels Lisa , Waller Ross F. , Lilley Kathryn S. , Wallace Chris , Crook Oliver M. , Kirk Paul D.W.
Published: February 2024

The subcellular localisation of proteins is a key determinant of their function. High-throughput analyses of these localisations can be performed using mass spectrometry-based spatial proteomics, which enables us to examine the localisation and relocalisation of proteins. Furthermore, complementary data sources can provide additional sources of functional or localisation information. Examples include protein annotations and other high-throughput ‘omic assays. Integrating these modalities can provide new insights as well as additional confidence in results, but existing approaches for integrative analyses of spatial proteomics datasets are limited in the types of data they can integrate and do not quantify uncertainty. Here we propose a semi-supervised Bayesian approach to integrate spatial proteomics datasets with other data sources, to improve the inference of protein sub-cellular localisation. We demonstrate our approach outperforms other transfer-learning methods and has greater flexibility in the data it can model. To demonstrate the flexibility of our approach, we apply our method to integrate spatial proteomics data generated for the parasiteToxoplasma gondiiwith time-course gene expression data generated over its cell cycle. Our findings suggest that proteins linked to invasion organelles are associated with expression programs that peak at the end of the first cell-cycle. Furthermore, this integrative analysis divides the dense granule proteins into heterogeneous populations suggestive of potentially different functions. Our method is disseminated via the mdir R package available on the lead author’s Github.

Author summary

Proteins are located in subcellular environments to ensure that they are near their interaction partners and occur in the correct biochemical environment to function. Where a protein is located can be determined from a number of data sources. To integrate diverse datasets together we develop an integrative Bayesian model to combine the information from several datasets in a principled manner. We learn how similar the dataset are as part of the modelling process and demonstrate the benefits of integrating mass-spectrometry based spatial proteomics data with timecourse gene-expression datasets.
Hamster (Cricetus cricetus) and ground squirrel (Spermophilus citellus) in the metropolitan area of Vienna, Austria: Urban development vs. species protection
Authors: Rubel Franz
Published: February 2024

Although European hamsters and European ground squirrels are listed as critically endangered on theIUCN Red List of Threatened Species, their habitats are becoming increasingly smaller due to the rapid expansion of the city of Vienna. The distribution of both species over the period 2000–2023 was documented by compiling a map based on georeferenced data from scientific monitoring and citizen science collections. Based on this, the population sizes in the metropolitan area of Vienna were estimated at 4000 hamsters and 16000 ground squirrels. An overview map was also created for each of the two species, which contains the names of the most important local occurrences. Satellite images were used to document populations that became extinct during the study period or in which animals lost large parts of their traditional habitat due to new urban development. This is considered particularly important in terms of conservation, as future generations would otherwise see the absence of wildlife in cities as normal, an effect known as shifting baseline syndrome. The Court of Justice of the European Union clarified key concepts for strict species protection. These also include eco-offsetting, i.e. creating habitats to replace ones lost to development, which was already applied before a recent construction project was implemented. On the occasion of this project, the application of eco-offsetting to protect the local ground squirrel population was documented and critically discussed.
Impaired transitioning of the FXR ligand binding domain to an active state underlies a PFIC5 phenotype
Authors: Behrendt Annika , Stindt Jan , Pfister Eva-Doreen , Grau Kathrin , Brands Stefanie , Bastianelli Alex , Dröge Carola , Stalke Amelie , Bonus Michele , Sgodda Malte , Cantz Tobias , Franke Sabine , Baumann Ulrich , Keitel Verena , Gohlke Holger
Published: February 2024

Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as agonists on FXR, which transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a PFIC5 patient, is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets BSEP and SHPin vitroand within the patient’s liver. Analysis of the structural dynamics of the conformational change from an inactive to an active state of the FXR LBD with molecular dynamics simulations revealed that while the wildtype protein frequently transitions into the active state, this movement and the necessary perfect placement of helix 12 was significantly impeded in the T296I mutated protein. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR. Overall, combiningin vivodata within vitroandin silicoexperiments, we suggest a molecular mechanism underlying the PFIC phenotype of a patient with an FXR missense variant.
The Fossilised Birth-Death Model is Identifiable
Authors: Truman Kate , Vaughan Timothy G , Gavryushkin Alex , Gavryushkina Alexandra “Sasha”
Published: February 2024

Time-dependent birth-death sampling models have been used in numerous studies for inferring past evolutionary dynamics in different areas, e.g. speciation and extinction rates in macroevolutionary studies, or effective reproductive number in epidemiological studies. These models are branching processes where lineages can bifurcate, die, or be sampled with time-dependent birth, death, and sampling rates, generating phylogenetic trees. It has been shown that in some subclasses of such models, different sets of rates can result in the same distributions of reconstructed phylogenetic trees, and therefore the rates become unidentifiable from the trees regardless of their size. Here we show that widely used time-dependent fossilised birth-death (FBD) models are identifiable. This subclass of models makes more realistic assumptions about the fossilisation process and certain infectious disease transmission processes than the unidentifiable birth-death sampling models. Namely, FBD models assume that sampled lineages stay in the process rather than being immediately removed upon sampling. Identifiability of the time-dependent FBD model justifies using statistical methods that implement this model to infer the underlying temporal diversification or epidemiological dynamics from phylogenetic trees or directly from molecular or other comparative data. We further show that the time-dependent fossilised-birth-death model with an extra parameter, the removal after sampling probability, is unidentifiable. This implies that in scenarios where we do not know how sampling affects lineages we are unable to infer this extra parameter together with birth, death, and sampling rates solely from trees.
Helicobacter pyloriseropositivity associates with hyperglycemia, but not obesity in Danish children and adolescents
Authors: Kløve Sigri , Stinson Sara E. , Romme Fie O. , Butt Julia , Graversen Katrine B. , Lund Morten A. V. , Fonvig Cilius E. , Waterboer Tim , Perez-Perez Guillermo I. , Hansen Torben , Holm Jens-Christian , Andersen Sandra B.
Published: February 2024

Helicobacter pyloricolonizes the human stomach and may affect the inflammatory response, hormone production related to energy regulation, and gut microbiota composition. Previous studies have demonstrated an inverse correlation betweenH. pyloriseropositivity and pediatric obesity. We hypothesized that we would find a similar relationship among Danish children and adolescents. We assessedH. pyloriseroprevalence in 713 subjects from an obesity clinic cohort and 990 subjects from a population-based cohort, and its association with obesity and other cardiometabolic risk factors. No association was found betweenH. pyloriand body mass index (BMI) standard deviation score (SDS).H. pyloriseropositivity was, however, associated with higher fasting blood glucose levels and the prevalence of hyperglycemia, suggesting thatH. pylorimay contribute to impaired glucose regulation in Danish children and adolescents.

Graphical abstract