bluuebunny/crossref_metadata_2025 huggingface dataset:
GalNT2-mediated O-glycosylation affects pancreas development and function in mice
Authors: Mercanoglu Baris , Waschkowski Sissy-Alina , Neuburg Elena , Schraps Nina , Giannou Anastasios D. , Dreyer Benjamin , Harder Sönke , Heine Markus , Krebs Christian F. , Güngör Cenap , Schlüter Hartmut , Melling Nathaniel , Hackert Thilo , Bockhorn Maximilian , Wagener Christoph , Wolters-Eisfeld Gerrit
Published: November 2024

GALNT2, also known as polypeptide N-acetylgalactosaminyltransferase 2, is an enzyme that catalyzes the initial step of O-linked glycosylation, a crucial posttranslational modification that affects protein folding, stability, and function. Alterations in GALNT2 activity have been implicated in various diseases, such as cancer, metabolic disorders, and cardiovascular diseases, highlighting its importance in maintaining normal physiological functions. To investigate the impact of GalNT2 overexpression in vivo for the first time, we generated a conditional transgenic mouse line in which GalNT2 was expressed specifically in the pancreas. Heterozygous overexpression leads to a loss of acinar mass and pancreatic steatosis, whereas homozygous overexpression causes complete pancreatic loss and results in a lethal phenotype. Using a reporter gene mouse line, we demonstrated that adipocytes originate through transdifferentiation from pancreatic cells. GalNT2 overexpression results in additional O-glycosylation sites, which we analyzed through PNA lectin enrichment and mass spectrometric proteome analysis.
Habitual physical activity is related to more creative activities and achievements
Authors: Rominger Christian , Fink Andreas , Perchtold-Stefan Corinna M. , Benedek Mathias , Schwerdtfeger Andreas R.
Published: November 2024

Beyond health, physical activity (PA) is associated with better creative ideation performance. People who are habitually more physically active produce more original ideas when asked to think creatively about an alternative use of an everyday object such as a brick. This aligns with findings indicating a positive relationship of PA with more basic cognition, such as memory, attention, as well as executive functioning. However, to the best of our knowledge, to date, no empirical research examined the link between PA (or inactivity) and real-life creative behavior. Therefore, this study investigated how objective and subjective assessments of PA relate to creative activities and achievements. In a sample of 156 participants wearing a mobile sensor for up to five consecutive days, less sedentary behavior and more moderate-to-vigorous PA were associated with more frequent creative activities. A similar pattern of associations occurred for self-rated habitual PA, which explained additional and unique variance of creative activities as well as creative achievements. For objective PA (assessed via sensor), we did not find associations with creative achievements, openness, and creative behavior. The results of this study suggest that the positive effects of habitual PA may generalize from better health, cognition, and creative ideation performance outcomes to more real-life creative behavior such as cooking original dishes and making music.
A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome
Authors: Trancuccio Alessandro , Tarifa Carmen , Bongianino Rossana , Priori Silvia G. , Santiago Demetrio J.
Published: November 2024

Timothy syndrome type 1 (TS1), a malignant variant of Long QT Syndrome, is caused by L-type Ca2+ Channel (LTCC) inactivation defects secondary to the p.Gly406Arg mutation in the CACNA1C gene. Leveraging on the experimental in vitro data from our TS1 knock-in swine model and their wild-type (WT) littermates, we first developed a mathematical model of WT large white swine ventricular cardiomyocyte electrophysiology that reproduces a wide range of experimental data, including ionic current properties, action potential (AP) dynamics, and $$\hbox {Ca}^{2+}$$

Ca

2
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handling. A sensitivity analysis tested robustness and facilitated comparison with the parent ORd human model. Introducing 22% of TS1-mutated LTCCs, the model faithfully reproduced key disease features, including marked AP prolongation, steeper rate-dependent adaptation of AP duration, $$\hbox {Ca}^{2+}$$

Ca

2
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overload, and CaMKII-mediated decreased upstroke velocity. Translational relevance of the TS1 model was investigated by: dissecting the roles of primary and secondary contributors to TS1 phenotype; demonstrating the arrhythmogenic potential of TS1 vs. WT cells; and evaluating the model’s capability to identify novel pharmacological targets which could modulate the cellular phenotype. In conclusion, we developed a mathematical large white swine ventricular myocyte model, demonstrating its utility in exploring arrhythmogenic mechanisms and therapeutic interventions in cardiac diseases, such as TS1.
Machine learning analysis of the effects of COVID-19 on migration patterns
Authors: Mukhamedova Farzona , Tyukin Ivan
Published: November 2024

This study investigates the impact of the COVID-19 pandemic on European tourist mobility patterns from 2019 to 2021 by conceptualizing countries as monomers emitting radiation to model and analyze their patterns through the lens of socio-economics and machine learning. By incorporating perturbations into clustering, this work evaluates the stability of mobility flux clustering under variable conditions, offering insights into the dynamics of socio-economic corridors. The results highlight distinct shifts in tourist behavior, with bimodal clustering in 2019 reflecting heterogeneous mobility patterns, whereas unimodal distributions in 2020 and 2021 indicate increased global uniformity, driven by pandemic-induced restrictions and gradual recovery. The PCA and dendrograms of the perturbed clustering reveal that tourist preferences align with GDP, cultural, and linguistic similarities, explaining regional cohesion and fragility. This study demonstrates the fragility of emerging socio-economic corridors like the Red Octopus compared to the resilience of established ones like the Blue Banana. The findings emphasize the importance of targeted policy interventions, such as strengthening transport infrastructure and fostering small and medium-sized enterprises (SMEs), to mitigate disruptions and promote balanced regional development. By integrating perturbations into clustering, this research introduces a strong framework for assessing mobility patterns under realistic variability to enhance economic resilience and anticipate shifts in tourist behavior during global crises.
A deep learning approach to real-time Markov modeling of ion channel gating
Authors: Oikonomou Efthymios , Juli Yannick , Kolan Rajkumar Reddy , Kern Linda , Gruber Thomas , Alzheimer Christian , Krauss Patrick , Maier Andreas , Huth Tobias
Published: November 2024

The patch-clamp technique allows us to eavesdrop the gating behavior of individual ion channels with unprecedented temporal resolution. The signals arise from conformational changes of the channel protein as it makes rapid transitions between conducting and non-conducting states. However, unambiguous analysis of single-channel datasets is challenging given the inadvertently low signal-to-noise ratio as well as signal distortions caused by low-pass filtering. Ion channel kinetics are typically described using hidden Markov models (HMM), which allow conclusions on the inner workings of the protein. In this study, we present a Deep Learning approach for extracting models from single-channel recordings. Two-dimensional dwell-time histograms are computed from the idealized time series and are subsequently analyzed by two neural networks, that have been trained on simulated datasets, to determine the topology and the transition rates of the HMM. We show that this method is robust regarding noise and gating events beyond the corner frequency of the low-pass filter. In addition, we propose a method to evaluate the goodness of a predicted model by re-simulating the prediction. Finally, we tested the algorithm with data recorded on a patch-clamp setup. In principle, it meets the requirements for model extraction during an ongoing recording session in real-time.
Utilizing photosynthetic oxygen-releasing biomaterials to modulate blood vessel growth in the chick embryo chorioallantoic membrane
Authors: Wang Zhaojun , Miao Xiaoping , Wu Xizhi , Wu Yongqi , Han Tengteng , Su Yude , Liu Peng , Zhu Zhiqiang , Xu Ronald X.
Published: November 2024

Utilizing photosynthetic oxygen-releasing biomaterials to promote increased blood vessel development on the chick embryo chorioallantoic membrane.
Development and antibacterial evaluation of a dopamine-modified curcumin@zinc-based organic framework
Authors: Qin Jiayi , Zhang Haiyan , Cao Xianying , Wen Feng , Jiang Ke
Published: November 2024

The elimination of S. aureus was achieved through the synergy of chemo, photothermal therapy (PPT), and Zn2+.
Efficient inverse CO2/C2H2 separation driven by difference in rare thermodynamic affinities in a porous MOF
Authors: Duan Hai-Yu , Li Xiu-Yuan , Hou Lei , Liu Si-Ru , Liu Xiang-Yu , Wang Ping
Published: November 2024

A new porous MOF featuring plentiful open metal sites in channels can achieve efficient inverse CO2/C2H2 separation, owing to uncommon higher thermodynamic affinities for CO2 than C2H2.
Total synthesis of (–)-rhynchine A, (+)-rhynchine C and (+)-rhynchine E
Authors: Cao Yinghao , Lu Xian , Li Yuan-Yang , Huang Lihua , Gao Beiling
Published: November 2024

Reported herein is the first enantioselective total synthesis of (–)-rhynchine A, (+)-rhynchine C and (+)-rhynchine E via a convergent strategy in 11 steps.
Recent advances in catalytic asymmetric condensation reactions for the synthesis of nitrogen containing compounds
Authors: Jia Jifan , Xu Qianqian , Fan Haitong , Lv Yunpeng , Li Dan
Published: November 2024

Asymmetric synthesis of functionalized nitrogen-containing compounds via the direct condensation of amines with carbonyls, focusing on the desymmetrization or dynamic kinetic resolution, the de novo cycloaromatization and the Heyns rearrangement.
Master–slave strategy based on fuzzy control for SOC recovery in the BESS FM process
Authors: Li Ningning , Chen Meiru , Ban Mingfei , Liu Yiqi
Published: November 2024

Conventional units can regulate grid frequency but often face challenges such as slow response times and accelerated aging. As a solution for frequency modulation (FM), the battery energy storage system offers a promising alternative, enabling efficient frequency regulation while maintaining the state of charge (SOC) within an optimal range. This article proposes a master–slave FM strategy based on fuzzy control to facilitate SOC restoration during the FM process. Initially, the principles of FM for both control types are examined, focusing on the output characteristics of virtual sag control and virtual inertia control. Subsequently, a collaborative output approach combining sag control and inertia control is presented as the primary FM strategy, where frequency changes are analysed, and frequency deviations and SOC are regionally categorized. An adaptive regulator is then designed to dynamically allocate weights to the outputs of the sag and inertia slave FM controls. Finally, simulation results validate the effectiveness and feasibility of the proposed master–slave FM strategy. Under conditions of continuous load disturbance, the strategy demonstrates a 4.07% improvement in SOC recovery compared to conventional control strategies that coordinate outputs through sag and inertia control.
A belief propagation algorithm based on track‐before‐detect for tracking low‐observable and manoeuvering targets using multiple sensors
Authors: Cao Chenghu , Huang Haisheng , Li Xin , Zhao Yongbo
Published: November 2024

It is notoriously challenging work to track an unknown number of low‐observable manoeuvering targets. In this paper, a sequential Bayesian inference method based on the multiple‐model dynamic model and track‐before‐detect measurement (TBD) model is proposed for tracking low‐observable manoeuvering targets using multiple sensors. The multiple‐model dynamic model is capable to characterise the dynamic behaviour of manoeuvering targets. The TBD measurement model can completely capture an echo signal without any preprocessing, furtherly handling with low‐observable targets. The authors’ proposed method is based on a new multi‐sensor statistical model that allows targets to interact and contribute to more than one data cell for the pixeled image TBD approach. Based on the factor graph representing the multi‐sensor statistical model, the marginal posterior densities are derived by performing the message passing equations of the proposed belief propagation algorithm for target detection and target state estimation. The simulation results validate that the computational complexity of our proposed multi‐sensor BP‐TBD algorithm scales in the number of sensor nodes and demonstrate that its performance is superior among the state‐of‐the‐art multi‐sensor TBD methods.
Transplacental Transport Rates of Anti-pertussis Toxin–IgG and Anti-filamentous Hemagglutinin–IgG Antibodies in Newborns by Week of Birth
Authors: Inceli Oguzhan , Sonmez Cemile , İnceli Elif Ece , Topçu Hasan Onur , Ibanoglu Mujde Can , Engin-Ustun Yaprak
Published: November 2024

Objective The aim of this study is to investigate the lack of knowledge about the transplacental transport of antibodies in unvaccinated term and preterm infants and possible differences in antibody-mediated immunity in the fetus depending on maternal vaccination in their own infancy.

Study Design The study was conducted as a prospective cross-sectional study between 2017 and 2018 and included a total of 334 participants. The study included 194 pregnant women with a preterm birth (before 37 weeks) and 140 pregnant women with a term birth. Both umbilical cord blood and maternal blood were used to measure serum levels of anti-pertussis toxin (PT) immunoglobulin (Ig) G and anti-filamentous hemagglutinin (FHA) IgG.

Results The results showed that anti-FHA IgG antibody levels in the cord blood of women who had delivered at term were significantly higher than those of preterm infants (p = 0.002). The placental transfer rate of anti-PT IgG was higher in women who delivered prematurely, but this difference was not statistically significant (p = 0.128). However, transfer rates for anti-FHA were significantly higher in women who had delivered prematurely (p = 0.001). In addition, transmission rates for both antibodies were found to be significantly lower in women who delivered before 32 weeks gestation than in women who delivered at term (p = 0.006, p < 0.001). Antibody transfer rates were found to be positively correlated with both gestational age and birth weight.

Conclusion In summary, although placental antibody transfer rates increased with gestational age, transfer rates and antibody levels were low in pregnant women, particularly in women who had given birth before 32 weeks gestation.

Key Points
Novel Placental Biomarker Shows Predictive Potential for Spontaneous Preterm Labor
Authors: Wang Bingbing , Seif Karl , Lei Jun , Mangione Mary , Turan Sifa , Reece E Albert , Burd Irina , Yang Peixin
Published: November 2024

Objective Human parturition involves many events among mother, fetus, and placenta, and the initiation of these events is the consequence of activation of a series of endocrine and immune responses. Multiple underlying pathways account for the cascade of events that culminate in spontaneous preterm labor. In this study, we aimed to characterize these signaling pathways of placental origin at molecular levels.

Study Design We used single-cell RNA-sequencing (sc-RNA-seq) analysis to probe transcriptional heterogeneity in human placenta delivered at preterm or term and then used RNA in situ hybridization (RNA-ISH) assay on formalin-fixed paraffin-embedded (FFPE) placental tissues to validate these results.

Results By using sc-RNA-seq on villous cytotrophoblast (CTB) isolated from a preterm placenta, we found that signaling pathways implicated in the initiation of term or preterm labor including ferroptosis, kisspeptin (KISS1), and senescence were constitutively activated in distinct cellular clusters of these trophoblastic stem cells. RNA-ISH-based spatial gene expression profiling in FFPE tissues revealed that pregnancy-specific beta-1-glycoprotein 4 (PSG4), a potent molecular driver for cellular aging, was significantly increased in preterm placentas (N = 30) compared to their full-term counterparts (N = 9). Furthermore, PSG4 mRNA signals were predominantly detected in the villous syncytiotrophoblast and the discontinuous monolayer of CTB as well as the intervillous space where maternal blood circulates.

Conclusion Our study provides strong support for PSG4 overexpression serving as a biomarker for pregnant women at risk for preterm delivery, which can allow for the development of timely and clinical preventive strategies.

Key Points
Impact of Treatment Technique on Testicular Dose and Sexual Activity in Rectal Cancer Patients
Authors: Tejaswi-Siddappa Poornachandra , Sunkappa Shamsundar , Kunigal-Puttaswamy Jagannath , Katke Aradhana , Ramanand Nanda , Boraiah Thejaswini
Published: November 2024

Objective To estimate the incidental radiation dose delivered to the testicles in three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated arc therapy (VMAT) in rectal cancer patients and its impact on sexual activity using a quality-of-life questionnaire.

Materials and Methods The present study included 40 male patients, aged between 25 and 50 years. with locally-advanced rectal cancer, who would undergo neoadjuvant radiotherapy at a dose of 45 Gray (Gy) in 25 fractions (fr) in the supine position. Planning was performed for three techniques: 3DCRT, IMRT, and VMAT. The testicular dose, testicular volume, planning target volume (PTV), the distance of the tumor from the anal verge, and tumor thickness and length in each plan were recorded. A quality-of-life questionnaire pertaining only to sexual activity by the European Organization for Research and Treatment of Cancer–Quality of Life in Colorectal (EORTC QLQ-CR29) and the Functional Assessment of Cancer Therapy–Colorectal (FACT-C) were used to assess the posttreatment effect on sexual life.

Results The mean values for tumor length, thickness, and PTV were of 8.9 cm, 1.77 cm and 1,352 cm3 respectively. The mean dose to the right and left testicles (in centigray, cGy) were as follows: 3DCRT – 336.23 and 206.65; IMRT – 165.15 and 140.25; and VMAT – 209.2 and 229.2 respectively. A significant correlation was observed involving the PTV and testicular volume and the incidental testicular dose received. The questionnaire-based analysis of sexual activity included 31 patients who were alive, of whom 27 had resumed their normal sexual life 3 months after the treatment without difficulty (score 4).

Conclusion The IMRT showed a significant reduction in the testicular dose when compared to 3DCRT and VMAT. The PTV and testicular volume presented a statistically significant impact on the testicular dose, and the main reason for abstinence was nervousness about disease recurrence.
The landscape of dementia research in Brazil from 2010 to 2021: a Scopus-based bibliometric study
Authors: Ramos Ari Alex , Bertola Laiss , Mata Fabiana Araújo Figueiredo da , Miguel Andrew Christopher Claro , Oliveira Junior Haliton Alves de , Ferri Cleusa Pinheiro
Published: November 2024

Background Several studies have sought to investigate the trajectory of scholarly publications on dementia. Yet, there has been limited attention to contributions from Latin America.

Objective To provide a comprehensive overview of the literature output on dementia in Brazil.

Methods We conducted a Scopus-based literature search (2010–2021) for publications by authors affiliated with Brazil.

Results Out of 5,534 reports, 2,528 met the inclusion criteria. The annual growth rate of publications on dementia (9.9%, SD = 15.5) closely paralleled that of general health-related literature (6.7%, SD = 4.9). Most publications were categorized into the areas of diagnosis (33.4%) and disease mechanisms, origins, and models (32.7%). Epidemiological studies (4%), clinical trials (1%), and economic analyses (0.3%) are scarce. Based on the first affiliation of Brazil-affiliated authors, 89.3% of dementia output stemmed from Southeast (68.4%) and South (20.9%) of Brazil. Nonetheless, the state of São Paulo alone accounted for 41.1%, contributing to 60.1% of the Southeast. First and second authorships were predominantly held by female researchers, whereas male researchers occupied most of the second-to-last and last authorships. Overall, 1,812 (71.7%) were published in 346 foreign journals and 716 (28.3%) in 43 Brazilian journals. Notably, nearly half of the reports published in Brazil are concentrated in two journals: Dementia e Neuropsychologia (31.4%) and Arquivos de Neuro-Psiquiatria (15.2%).

Conclusion There is a pressing need for more studies in dementia epidemiology and economic cost, in addition to more research across all Brazilian regions.
Evaluation of the Effect of Topically Applied Resveratrol Gel as Adjunctive Treatment for Periodontitis
Authors: Hussein Mahmoud Hassan , Badr Bahaa Mohammed , Hassan Khalid Seddik , Ibrahim Ibrahim Hammad
Published: November 2024

Objective Our objective was to evaluate the impact of topically applied resveratrol (RES) gel as adjunctive to conventional periodontal therapy on both clinical periodontal parameters as well as to assess interleukin-1β (IL-1β) level in gingival crevicular fluid (GCF) in patients with stage I and II grade A periodontitis.

Materials and Method This study was performed on 40 cases aged from 26 to 47 years with means of (37.02 ± 6.88) of both sexes (16 females and 24 males) with stage І and П grade A periodontitis. They were divided into two groups: group Ι consisted of 20 cases with stage I and II grade A periodontitis who were treated only with conventional periodontal care (scaling and root planning [SRP]), and group Π consisted of 20 cases with stage I and II grade A periodontitis who were subjected to conventional periodontal therapy (SRP) in conjunction with intrapocket RES gel application. At baseline, 3 months, and 6 months following therapy, all patients had clinical evaluation using gingival index (GI), plaque index (PI), probing pocket depth (PPD), and clinical attachment level (CAL). Also, an enzyme-linked immune-sorbent assay-based biochemical analysis of IL-1β was conducted at baseline, 3 months, and 6 months.

Results Clinical findings were different significantly as correlated within the same group; however, there was no significant difference between both groups. Biochemical evaluation of IL1β revealed no significant variation at baseline and 3 months between both groups, while there was a significant difference during treatment at 6 months.

Conclusion Our findings indicate that RES as supplementary in addition to conventional periodontal therapy may improve periodontitis through anti-inflammatory effects.
Modified Lateral Supraorbital Craniotomy with Posterior Orbitotomy and Anterior Clinoidectomy for Resection of a Midline Planum and Tuberculum Sellae Meningioma
Authors: Stevens Baylee H. , Prather Kiana Y. , Bialek Shannan , Graffeo Christopher S.
Published: November 2024

The patient is a 51-year-old woman who had been experiencing syncope and near-syncopal events for at least 10 years with an otherwise benign neurological exam. Magnetic resonance imaging revealed an extra-axial mass consistent with a midline planum and tuberculum sellae meningioma, for which the patient opted to have resected. We demonstrate how performing a posterior orbitotomy with anterior clinoidectomy can enhance a lateral supraorbital craniotomy. The patient did well following surgery, with marked improvement in syncopal symptoms. Pertinent surgical anatomy and techniques are highlighted in this video demonstration.
The Evolution of Hemophilia Pharmacological Treatments and Therapeutic Targets at the Turn of the Third Millennium
Authors: Coppola Antonio , Zani Matteo , Quintavalle Gabriele , Focosi Daniele , Franchini Massimo
Published: November 2024

Historically, the aim of treatment for hemophilia, the congenital X-linked hemorrhagic disorder due to deficiencies of coagulation Factor (F) VIII (hemophilia A) or FIX (hemophilia B), has been the replacement through factor concentrates, whose regular administration (i.e., prophylaxis) has been shown to be highly effective in preventing bleeding complications and it is currently considered the gold standard of hemophilia treatment. However, continuous technological progress (i.e., plasma-derived factor concentrates, recombinant standard and extended half-life [EHL] products) has allowed clinicians operating at hemophilia treatment centers to individualize the management of persons with hemophilia, improving outcomes, adherence to therapy, and their quality of life. The achievement of normal hemostasis, the final goal that now seems possible with new-generation EHL products, non-replacement and gene therapies, will translate into normalization of life for persons with hemophilia, also addressing health equity (i.e., rendering them indistinguishable from their healthy peers). The evolution of hemophilia treatment and, in parallel, of therapeutic targets in the management of hemophilia patients over the last decades will be critically discussed in this narrative review.
Abdominal Tuberculosis in Children
Authors: Emiroglu Melike , Alkan Gulsum , Kiymaz Meltem , Tuter Oz Sadiye Kubra , Turk Dagi Hatice , Öztürk Mehmet , Çelik Zeliha Esin
Published: November 2024

Objective To provide an insight into the presentation, diagnosis, and management of gastrointestinal tuberculosis in children.

Methods We reviewed the medical records of children who were diagnosed with gastrointestinal tuberculosis, between October 2013 and October 2023. The analysis was performed using descriptive statistics.

Results During the study period, 11 of 76 tuberculosis pediatric patients (14.5%) were diagnosed with gastrointestinal tuberculosis. Six of 11 patients (54.5%) were female. The median age of the patients was 60 months (51–205 months). Eight of 11 patients had intra-abdominal lymph node involvement, 3 of 11 patients had intestinal tuberculosis, and 2 of 11 patients had also active pulmonary tuberculosis. Multiple intra-abdominal areas were involved in six patients. Mean duration of symptoms before admission was 60 days (5–180 days). The most common symptoms were abdominal pain (63.7%), weight loss (63.7%), and weakness/fatigue (54.5%). Acid-fast bacilli and tuberculosis polymerase chain reaction were positive in only two patients. Tuberculosis culture positivity was detected in two patients, both of them showed Mycobacterium bovis growth. Necrotizing granulomatous inflammation was the most frequently observed histopathological finding. Anemia was detected in six patients. There was elevated erythrocyte sedimentation rate in eight patients and elevated C-reactive protein in six patients. In one patient, recurrent obstruction symptoms developed due to stenosis of terminal ileum. Clinical cure was achieved with supportive treatment.

Conclusion Diagnosis of gastrointestinal tuberculosis is very difficult due to nonspecific clinical and radiological features. Microbiological confirmation of the disease is often challenging. Making a definitive diagnosis requires reliance on strong clinical suspicion, imaging and histopathological findings, microbiological tests, and/or response to treatment.
Comparison of Delta Neutrophil Index and Inflammatory Markers in the Diagnosis of Late-Onset Neonatal Sepsis in Preterm Infants
Authors: Yazici Aybuke , Kanmaz Kutman Hayriye Gozde , Kadioglu Simsek Gulsum , Siyah Bilgin Betul , Canpolat Fuat Emre , Dinc Bedia , Oguz Serife Suna
Published: November 2024

Objective This study aimed to assess the performance of the relatively new hematological marker delta neutrophil index (DNI) and other inflammatory markers in proven sepsis of the very preterm infant.

Methods Infants with a gestational age of <32 weeks, who were examined retrospectively for suspected late-onset sepsis (LOS), were evaluated in the study.. Demographic characteristics, laboratory findings, and neonatal morbidity and mortality were compared between infants with blood culture-confirmed sepsis and clinical sepsis.

Results The study included 358 infants, 90 with proven sepsis and 268 with clinical sepsis. The mean gestational ages in these groups were 28.2 ± 2 and 28.2 ± 2.1 weeks, and the mean birth weights were 1139 ± 372 and 1148 ± 370 g, respectively (p > 0.05). The proven sepsis group had higher DNI (median 7.1% [range: 0.1–74] vs. 0.6% [range: 0.1–24.7%], p < 0.01], C-reactive protein (CRP; median 5 [range: 1–38] mg/L vs. 1 [range: 1–15] mg/L, p < 0.001), interleukin-6 (median 620 [range: 6.9–5,500] pg/mL vs. 42.2 [range: 2.2–5500] pg/mL, p < 0.01), and procalcitonin (median 6.2 [range: 0.26–86] µg/L vs. 0.6 [range: 0.06–25.7] µg/L, p = 0.002). According to receiver operating characteristic curve analysis, interleukin-6 had the highest area under the curve (AUC) at 0.74 (95% CI: 0.60–0.88, p < 0.01). The AUC values were 0.73 (95% CI: 0.59–0.88, p = 0.01) for procalcitonin, 0.62 (95% CI: 0.44–0.80, p = 0.18) for DNI, and 0.66 (95% CI: 0.50–0.82, p = 0.05) for CRP.

Conclusion The DNI showed a statistically significant elevation in infants with proven sepsis; however, its diagnostic performance was lower than that of interleukin-6, CRP, and procalcitonin. Although the results are encouraging in determining the utility of DNI in predicting LOS in preterm infants, further research is needed to validate its predictive value, specifically in this population.
A new approach to study stochastic epigenetic mutations in sperm methylome of Vietnam war veterans directly exposed to Agent Orange
Authors: Corsaro Luigi , Sacco Davide , Corbetta Carlo , Gentilini Davide , Faversani Alice , Ferrara Fulvio , Costantino Lucy
Published: November 2024

Among the various environmental pollutants, dioxin, a highly toxic and widely used compound, is associated with numerous adverse health effects, including a potentially toxic multigenerational effect. Understanding the mechanisms by which dioxin exposure can affect sperm epigenetics is critical to comprehending the potential consequences for offspring health and development. This study investigates the possible association between weighted epimutations, hypothesized as markers of epigenetic drift, and dioxin exposure in sperm tissues. We used a public online methylation dataset consisting of 37 participants: 26 Vietnam veterans exposed to Agent Orange, an herbicide contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 11 individuals not directly exposed to TCDD but whose serum dioxin levels are equivalent to the background. In our study, conducted at the gene level, 437 epimutated genes were identified as significantly associated with each single-digit increase in serum dioxin levels. We found no significant association between the rise in total epimutation load and serum dioxin levels. The pathway analysis performed on the genes reveals biological processes mainly related to changes in embryonic morphology, development, and reproduction. Results from our current study suggest the importance of further investigations on the consequences of dioxin exposure in humans with specific reference to germinal tissue and related heredity.
A review of antimicrobial stability testing guidance for outpatient parenteral antimicrobial therapy programmes: is it time for global harmonization of testing frameworks?
Authors: Naicker Saiyuri , Roberts Jason A , Cheng Vesa , Parker Suzanne L , Seaton R Andrew , Gilchrist Mark , Sime Fekade B
Published: November 2024

Antimicrobial stability is an important consideration for treatment planning and service delivery in outpatient parenteral antimicrobial therapy (OPAT) programmes. Regulation of stability assessment varies by region, and conflicting guidance and standards exist. This leads to disparity of equity in access and limits availability of certain antimicrobials for managing infections in the outpatient setting. This review discusses the degree to which the international regulatory bodies have reached consensus on the regulation of antimicrobial stability testing, specifically for OPAT, and describes the variation in antimicrobial recommendations across regulatory bodies. The three major findings in this review are (i) variation in antimicrobial stability testing guidance, particularly in relation to temperature; (ii) lack of regulatory guidance, specifically in that some regions did not have OPAT guidelines; and (iii) only the UK’s NHS has provided non-regulatory OPAT-specific advice on antimicrobial stability testing. In conclusion, harmonization of antimicrobial stability testing to form a global OPAT-specific regulatory framework, particularly considering ‘areas of variation’ amongst current guidance, is required. We call for the development of a global OPAT antimicrobial stability testing framework with consensus from accepted antimicrobial stability criteria, expert opinion and pharmacopoeial best practice.
Bone marrow mesenchymal stem cell‐derived exosomal miR‐181a‐5p promotes M2 macrophage polarization to alleviate acute pancreatitis through ZEB2‐mediated RACK1 ubiquitination
Authors: Li Hanyu , Du Ruifeng , Xiang Andong , Liu Yankui , Guan Ming , He Hongchun
Published: November 2024

As a common digestive disease, acute pancreatitis (AP) often threatens the life of patients. Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have exhibited some benefits for AP. However, the mechanism remains unclear and deserves to be further investigated. The characteristics of BMSCs‐exosomes (BMSCs‐Exos) were identified. The abundance of genes and proteins was evaluated using quantitative real‐time PCR (RT‐qPCR), western blot, enzyme‐linked immunosorbent assay (ELISA) and IF assay. Cell apoptosis and CD206‐positive cells were measured by flow cytometry. The interactions among miR‐181a‐5p, Zinc finger E‐box binding homeobox 2 (ZEB2) and Receptor for Activated C Kinase 1 (RACK1) were verified using dual luciferase reporter assay, RNA immunoprecipitation (RIP), coimmunoprecipitation (Co‐IP). BMSCs‐Exos effectively improved AP injury through restraining AR42J cell apoptosis and promoting M2 macrophage polarization, which was realized due to BMSCs‐Exos harboring an abundance of miR‐181a‐5p. Further experiments validated miR‐181a‐5p silenced ZEB2 and ZEB2 reduced RACK1 expression through mediating RACK1 ubiquitination. ZEB2 knockdown decreased AR42J cell apoptosis and induced M2 macrophage polarization to alleviate AP injury, whereas RACK1 downregulation abolished these phenomena. BMSCs‐Exos harboring miR‐181a‐5p suppressed AR42J cell apoptosis and promoted M2 macrophage polarization to delay AP progression through ZEB2‐mediated RACK1 ubiquitination.
The central role of creatine and polyamines in fetal growth restriction
Authors: Di Giorgio Eros , Xodo Serena , Orsaria Maria , Mariuzzi Laura , Picco Raffaella , Tolotto Vanessa , Cortolezzis Ylenia , D'Este Francesca , Grandi Nicole , Driul Lorenza , Londero Ambrogio , Xodo Luigi E.
Published: November 2024

Placental insufficiency often correlates with fetal growth restriction (FGR), a condition that has both short‐ and long‐term effects on the health of the newborn. In our study, we analyzed placental tissue from infants with FGR and from infants classified as small for gestational age (SGA) or appropriate for gestational age (AGA), performing comprehensive analyses that included transcriptomics and metabolomics. By examining villus tissue biopsies and 3D trophoblast organoids, we identified significant metabolic changes in placentas associated with FGR. These changes include adaptations to reduced oxygen levels and modifications in arginine metabolism, particularly within the polyamine and creatine phosphate synthesis pathways. Specifically, we found that placentas with FGR utilize arginine to produce phosphocreatine, a crucial energy reservoir for ATP production that is essential for maintaining trophoblast function. In addition, we found polyamine insufficiency in FGR placentas due to increased SAT1 expression. SAT1 facilitates the acetylation and subsequent elimination of spermine and spermidine from trophoblasts, resulting in a deficit of polyamines that cannot be compensated by arginine or polyamine supplementation alone, unless SAT1 expression is suppressed. Our study contributes significantly to the understanding of metabolic adaptations associated with placental dysfunction and provides valuable insights into potential therapeutic opportunities for the future.
Cutting a nerve of the hand alters the organisation of digit maps in primary somatosensory cortex
Authors: Weber Martin , Marshall Andrew , Timircan Ronan , McGlone Francis , Tucciarelli Raffaele , Onyekwelu Obi , Booth Louise , Jesudason Edwin , Lees Vivien , Valyear Kenneth F.
Published: November 2024

Hand nerve transection injuries precipitate a variety of reorganisational changes in both the peripheral and central nervous systems. Surgical repair restores the continuity of severed nerves, yet regenerating fibres establish new connections without topographical guidance, rearranging the branching architecture of peripheral nerves in the hand.

In non-human primates, forelimb nerve transection and repair dramatically alters the otherwise orderly and highly conserved organisation of the digit maps in primary somatosensory areas 3b and 1. Digit-map organisation becomes patchwork and highly variable. Although without compelling evidence, these same reorganisational changes are presumed to occur in humans and to have significant functional implications for patient recovery. In the current study, we evaluate these assumptions.

Functional MRI is used to characterise the fine-grained organisation of digit responses in the primary somatosensory cortex in twenty-one patients with nerve transection injuries and thirty healthy controls. Both univariate dice ‘overlap’ coefficients and state-of-the-art multivariate representational distances are used to quantify the extent and pattern of interdigit response separability in primary somatosensory cortex. Our results reveal significant differences between patients and controls. The fine-grained organisation of the primary somatosensory cortex is altered in nerve repair. Average dice coefficients reveal significantly increased interdigit response overlap. These effects are specific to the hemisphere contralateral to the nerve-repaired hand, reflecting inputs from reinnervated digits, and are more robust within the cortical zones of the repaired nerves. Nerve repair also alters the relative functional structure of the primary somatosensory cortex, changing the otherwise stereotypical pattern of interdigit response separability seen in healthy controls. Unexpectedly, these later alterations manifest bilaterally, as maps for the healthy hand of patients also show an atypical pattern of interdigit response separability.

Our findings provide the first compelling evidence for altered digit maps following nerve repair in humans, bridging results from animal models. Nonetheless, the clinical significance of the changes we observe remains unclear. No reliable relationships between fMRI measures of cortical reorganisation and behavioural measures of functional impairments are observed. Altered digit maps are not found to correlate with impairments in touch localisation or with broader measures of functional impairment as captured by sensory Rosen scores.
Increased Prevalence of Oxytocin Receptor Gene Variant in Functional Neurological Disorder: A Preliminary Case-Control Study
Authors: Weber Samantha , Stoffel Natascha , Rey Álvarez Lucía Trinidad , Ansede-Bermejo Juan , Cruz Raquel , Del Real Bolt Álvaro , Bühler Janine , Carracedo Ángel , Aybek Selma
Published: November 2024

Background

Current models on functional neurological disorders (FND) propose a multifactorial origin. Recent studies identified potential biological vulnerability factors – such as a reduced limbic volume or an altered stress response. These findings highlight the need to investigate a potential genetic contribution to the biological vulnerability to FND.

Method

Eighty-five mixed FND patients and seventy-six healthy controls (HC) were genotyped for ten single nucleotide polymorphisms within seven genes associated with the stress system. For the genetic variant that was found to be associated with FND, further associations to structural brain alterations were investigated using a region-of-interest approach. Regions were previously selected based on their biological involvement and as a vulnerability for FND.

Results

A significant association between the diagnosis of FND and the rs53576 of the oxytocin receptor (OXTR) gene was found. A significant association between decreased right insular volumes and rs53576 (OXTR) was identified in FND patients. In female patients, the rs53576 (OXTR) was associated with a reduced bilateral amygdalar volume.

Conclusion

These preliminary results suggest a genetic contribution to the biological vulnerability for FND involving the oxytocinergic system, and (sex-specific) structural changes in insula and amygdala.
Trends and patterns of sedative prescribing in primary care in Ireland between 2014 and 2022 - a repeated cross-sectional study
Authors: Mattsson Molly , Ali Ahmed Hassan , Boland Fiona , Flood Michelle , Kirke Ciara , Wallace Emma , Corrigan Derek , Walsh Mary E , Fahey Tom , Moriarty Frank
Published: November 2024

Background

The trends in sedative use have varied in recent years. Benzodiazepines and z-drugs are indicated for anxiety and sleep disorders, but should be limited to short term use. The aim of this study is to examine trends and patterns in sedative prescribing in Ireland between 2014 and 2022, as well as comparing trends between Ireland and England within the same period.

Methods

Monthly data on medicines prescribed and dispensed in primary care on the means-tested General Medical Services (GMS) scheme in Ireland was used. Volumes of prescribed benzodiazepine and z-drug use and patterns of prescribing, including initiations, discontinuations, chronic use, and high-risk prescribing were summarised per year. Other sedating agents (sedating antihistamines, antidepressants, and antipsychotics) were also analysed. Volume of use outcomes were compared with NHS data from England for the same period.

Results

The rate of benzodiazepine and z-drug dispensings per 1,000 GMS population decreased by 4%, from 1,531 in 2014 to 1,474 in 2022. T By comparison in England, there was a steeper decrease of 27% in the dispensing rate and the level of use was substantially lower, falling from 288 dispensings per 1,000 population in 2014 to 210 in 2022. In Ireland, dispensing rates were highest amongst women and older age groups. High-risk dispensings of benzodiazepines and z-drugs decreased over the study period

Discussion

Despite decreases in benzodiazepine and z-drug dispensings, rates remain high in Ireland and may suggest a need for enhanced availability of non-pharmacological interventions, and improved education and deprescribing support for healthcare professionals.

Statement of Significance

The use of benzodiazepines and z-drugs has decreased in many populations in recent years, while prescribing of other sedatives has increased. In Ireland, comparatively higher levels of prescribing have been previously identified. Describing and quantifying medication use is important to monitor medication safety at the population level, however this can be complex and therefore a range of indicators are needed to capture differences.

The findings of this study suggest that benzodiazepine and z-drug dispensing is decreasing in Ireland, including high-risk dispensings and dispensings to older age groups. However, in comparison to England, dispensing rates remain high and suggest a need for enhanced availability of non-pharmacological services and interventions, as well as improved education and deprescribing support for healthcare professionals.
AEGIS: individual-based modeling of life history evolution
Authors: Bagic Martin , Šajina Arian , Bradshaw William John , Valenzano Dario Riccardo
Published: November 2024

Nature presents a staggering diversity of life history strategies, ranging from rapid to slow onset of sexual maturity, short or long life, low or high number of offspring, and much more. Each species-specific life history trait reflects on the one hand specific adaptations to unique environments, e.g., nutrient availability, predation, parasite load, seasonality; and on the other hand, depends on past demographic constraints, such as population bottlenecks, migrations, etc. Studying life history diversity in nature and in the laboratory ultimately aims to identify the ecological, demographic, and intrinsic causes contributing to species-specific growth rate distributions, lifetime reproductive outcomes, as well as lifespans. However, for most species, we cannot rewind the evolutionary and demographic past to identify the causal chain of events leading to the present life history traits. We can infer past events only by sampling extant populations.In silicoevolution has the advantage of providing complete time resolution for the events driving life history evolution and enables to directly test the impact of ecological and demographic variables on the evolution of life history traits. We developed AEGIS (Aging of Evolving Genomes In Silico), a software for individual-based modeling of life history trait evolution at the genotype and phenotype level. AEGIS models life history traits evolution in response to a set of factors, including resource availability, extrinsic mortality induced by predators or parasites, different levels of germline mutation rates, population size, sexual vs. asexual reproduction, and more. AEGIS serves as a powerful tool to model life history evolution and allows for parameter inference against ground truths. AEGIS can help generate estimates for the evolution of different life history traits, such as age-dependent mortality and reproduction, in response to different selective pressures and intrinsic genetic constraints.