bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of BCR::ABL1 in laminin adhesion of Philadelphia chromosome‐positive acute lymphoblastic leukemia through upregulation of integrin α6
Authors: Takahashi Kazuya , Nguyen Thao Thu Thi , Watanabe Atsushi , Sato Hiroki , Saito Kinuko , Tamai Minori , Harama Daisuke , Kasai Shin , Akahane Koshi , Goi Kumiko , Kagami Keiko , Abe Masako , Komatsu Chiaki , Maeda Yasuhiro , Sugita Kanji , Inukai Takeshi
Published: April 2024

Background

Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with integrin β1 (CD29) or β4 (CD104) are major functional receptors for laminin. Higher CD49f expression is reportedly associated with a poorer response to induction therapy in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). Moreover, a xenograft mouse model transplanted with primary BCP‐ALL cells revealed that neutralized antibody against CD49f improved survival after chemotherapy.

Aims

Considering the poor outcomes in Philadelphia chromosome (Ph)‐positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion.

Methods and results

Ph‐positive ALL cell lines expressed the highest levels of CD49f among the BCP‐ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP‐ALL cell lines. The association of Ph‐positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph‐positive ALL cell lines attached to laminin and their laminin‐binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph‐positive ALL cell lines, but not in their T315I‐acquired sublines. Consistently, the laminin‐binding properties were disrupted by the imatinib pre‐treatment in the Ph‐positive ALL cell line, but not in its T315I‐acquired subline.

Conclusion

BCR::ABL1 plays an essential role in the laminin adhesion of Ph‐positive ALL cells through upregulation of CD49f.
A cross‐sectional study of sleep disturbance among middle‐aged cancer patients at Vietnam National Cancer Hospital
Authors: Pham Anh Tuan , Do Mai Tuyet , Tran Huong Thi Thanh
Published: April 2024

Aim

Sleep disorders are common in cancer patients and have negative consequences for patient well‐being and treatment outcomes. This study aimed to investigate sleep quality and related factors in Vietnamese middle‐aged cancer patients.

Methods

A cross‐sectional study was conducted on 246 middle‐aged in‐patient cancer patients at Vietnam National Cancer Hospital (VNCH) from 1/2021 to 7/2021. Sleep was measured by the Pittsburgh Sleep Quality Index (PSQI), with a cutoff of 5.

Results

The results showed a male/female ratio of 0.85 with an average age of 52. The five most prevalent cancer types were breast, colorectal, lung, and esophagus‐stomach cancer, primarily in the late stage and treated with chemotherapy. The prevalence of sleep disturbances was 58.5%. The mean PSQI score was 7.5, with sleep duration and latency of 5.4 h and 1 h, respectively. Approximately 44% of participants reported poor sleep quality, nearly 9% had daytime dysfunction, and 10.6% used sleep medication. The multivariate logistic regression results indicate that people with depression were 8.89 times more likely to have poor sleep than those without depression (95% CI:2.63–28.27, p < .001).

Conclusion

Sleep problems are common among middle‐aged people with cancer in Vietnam, especially individuals with depression. It is necessary to have more effective approaches to sleep management for cancer patients with limited resources.
An ELISA‐Based Method to Measure Mucosal Antibody Responses Against SARS‐CoV‐2 in Human Saliva
Authors: Bhavsar Disha , Sano Kaori , Singh Gagandeep , Krammer Florian
Published: April 2024

The primary mode of transmission for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is infection of the respiratory tract through droplets and/or aerosols. Therefore, immune responses at respiratory mucosal surfaces play a significant role in the prevention of infection. Greater emphasis is now being placed on mucosal immunity induced by exposure to SARS‐CoV‐2 antigens through infection or vaccination. In concert with cellular immunity, humoral responses at mucosal surfaces, especially the secretory version of immunoglobulin A (sIgA), can be instrumental in preventing respiratory infections. A better understanding of mucosal immune responses can further our knowledge of immunity to SARS‐CoV‐2 and help inform vaccine design. Here we describe a detailed protocol for an in vitro assay based on the enzyme‐linked immunosorbent assay (ELISA) to assess mucosal antibody response to SARS‐CoV‐2 spike protein in human saliva. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.

Basic Protocol: ELISA measurement of mucosal antibodies to SARS‐CoV‐2 spike protein in human saliva
The usefulness of texture and color enhancement imaging to identify the minor papilla orifice
Authors: Goda Yoshihiro , Irie Kuniyasu , Anan Hideyuki , Suzuki Yuichi , Ikeda Aya , Ikeda Ryosuke , Kaneko Hiroaki , Sue Soichiro , Miwa Haruo , Maeda Shin
Published: April 2024

In clinical cases of pancreas divisum, endoscopic retrograde cholangiopancreatography often necessitates cannulation of the pancreatic duct through the minor papilla. Nevertheless, this procedure can be challenging because of the small size of the minor papilla and the difficulty in visualizing the ductal orifice. A new image‐enhanced endoscopy technique called texture and color enhancement imaging (TXI) has been developed, which enhances texture, brightness, and color compared with white‐light imaging, resulting in subtle differences in the surface mucosa. Herein, we describe the case of a 73‐year‐old man with pancreas divisum in whom TXI was useful in identifying the orifice of the minor papilla. He was referred to our hospital with repetitive acute exacerbation of chronic pancreatitis. Since contrast‐enhanced computed tomography revealed a pancreatic stone in the main pancreatic duct, endoscopic retrograde cholangoepancreatography was performed as a therapeutic intervention. Despite the initial difficulty in identifying the orifice of the minor papilla on white‐light imaging, TXI enhanced its visibility successfully, enabling dorsal pancreatic duct cannulation via the minor papilla. Subsequently, endoscopic pancreatic sphincterotomy was performed and a 6Fr plastic stent was placed. Post‐endoscopic therapy, the patient's abdominal pain was relieved. TXI was useful in identifying the minor papilla orifice and led to successful cannulation.
Incidence and predictors of heart failure with reduced and preserved ejection fraction after ST‐elevation myocardial infarction in the contemporary era of early percutaneous coronary intervention
Authors: Lenselink Chris , Ricken Kim W.L.M. , Groot Hilde E. , de Bruijne Tijs J. , Hendriks Tom , van der Harst Pim , Voors Adriaan A. , Lipsic Erik
Published: April 2024

Aims

The development and incidence of de‐novo heart failure after ST‐elevation myocardial infarction (STEMI) in the contemporary era of rapid reperfusion are largely unknown. We aimed to establish the incidence of post‐STEMI heart failure, stratified by left ventricular ejection fraction (LVEF) and to find predictors for its occurrence. Furthermore, we investigated the course of left ventricular systolic and diastolic function after STEMI.

Methods and results

A total of 1172 all‐comer STEMI patients from the CardioLines Biobank were included. Patients were predominantly male (74.5%) and 64 ± 12 years of age. During a median follow‐up of 3.7 years (2.0, 5.5) we found a total incidence of post‐STEMI heart failure of 10.9%, of which 52.1% heart failure with reduced ejection fraction (HFrEF), 29.4% heart failure with mildly reduced ejection fraction and 18.5% heart failure with preserved ejection fraction (HFpEF). Independent predictors for the development of HFrEF were male sex (β = 0.97, p = 0.009), lung crepitations (β = 1.09, p = 0.001), potassium level (mmol/L, β = 0.43, p = 0.012), neutrophil count (109/L, β = 0.09, p = 0.001) and a reduced LVEF (β = 1.91, p < 0.001) at baseline. Independent predictors for the development of HFpEF were female sex (β = 0.99, p = 0.029), pre‐existing kidney failure (β = 1.95, p = 0.003) and greater left atrial volume index (β = 0.04, p = 0.033) at baseline. Follow‐up echocardiography (median follow‐up 20 months) showed an improvement in LVEF (p < 0.001), whereas changes in diastolic function parameters showed both improvement and deterioration.

Conclusion

In the current era of early STEMI reperfusion, still one in 10 patients develops heart failure, with approximately half of the patients with a reduced and half with a mildly reduced or normal LVEF. Predictors for the development of HFrEF were different from HFpEF.
Chiral resolution of cationic piperazine derivatives by capillary electrophoresis using sulfated β‐cyclodextrin
Authors: Niaei Navid , Hassanpour Soodabeh , Petr Jan
Published: April 2024

This research focuses on the development and validation of a capillary electrophoresis (CE) method for the chiral separation of three H1‐antihistamine drugs chlorcyclizine, norchlorcyclizine, and neobenodine using sulfated β‐cyclodextrin (S‐β‐CD) as the chiral selector. The study explores various factors influencing the separation efficiency, including CD concentration, organic modifier content, voltage application, and buffer pH. Optimal conditions were identified as a 100 mM phosphate buffer (pH 6.0) with 34 mg mL–1 S‐β‐CD and 40% (v/v) methanol. The method demonstrated excellent linearity in calibration curves, with coefficients of determination exceeding 0.99 for each enantiomer. Precision studies revealed good intra‐ and inter‐day precision for migration times and peak areas. The limits of detection and quantification for the analytes were within the ranges of 5.9–11.4 and 18–34.6 µmol L–1, respectively. Overall, the developed CE method offers a robust and precise approach for the chiral separation of H1‐antihistamine drugs, holding promise for pharmaceutical applications.
Chronically activated microglia in ALS gradually lose their immune functions and develop unconventional proteome
Authors: Barreto‐Núñez Romina , Béland Louis‐Charles , Boutej Hejer , Picher‐Martel Vincent , Dupré Nicolas , Barbeito Luis , Kriz Jasna
Published: April 2024

Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1‐G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age‐matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.
Job satisfaction of health workers at a Vietnamese University Hospital and its predicted factors: A cross‐sectional study
Authors: Sa Hoang Cao , Nhiem Nguyen Thi Thanh , Anh Bui Thi My , Thanh Nguyen Duc
Published: April 2024

Background and Aims

Job satisfaction of healthcare workers from conventional and university hospitals (or teaching hospitals) might be different due to several factors, for example medical staff required to carry out multiple clinical and teaching tasks simultaneously. Our study aimed to determine how the job satisfaction among healthcare workers in university hospitals is different from those in conventional hospitals.

Methods

A cross‐sectional study was conducted by using the validated and contextualized job satisfaction tool for the Vietnamese context to survey 216 healthcare workers at a university hospital in Vietnam from January to March 2020 with online Google forms.

Results

The results indicated low overall job satisfaction (43.1%) in our study university hospital with the score cutoff of 80%. However, healthcare workers still reported high job satisfaction rates in certain aspects, such as personal empathy (70.8%), discipline, and reward (67.6%), co‐worker collaboration (65.3%), training and promotion (63%), workplace environment (57.4%), and salary and allowance (44.9%). Subgroup analysis revealed statistically significant differences in job satisfaction (p < 0.01) related to age (31 to 40‐year‐old), and job position with ORs 3.9, and 8.6 respectively.

Conclusion

University hospitals need to improve the healthcare workers' job satisfaction. It is recommended that special human resource strategies should be developed focusing on keeping satisfying older healthcare staff by recognizing their contributions and providing appropriate benefits based on their positions in the hospital.
Impacts of male chromosomal polymorphisms on semen quality and IVF/ICSI outcomes: A retrospective cohort study
Authors: Lu Yongjie , Tian Tian , Chen Lixue , Yan Liying , Chang Liang , Qiao Jie
Published: April 2024

Objective

The study aims to elucidate the impacts of different types of male chromosomal polymorphisms (MCPs) on various outcomes of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment.

Methods

This retrospective cohort study included 1442 couples with normal karyotypes, 1442 couples with MCPs, 42 couples with male chromosomal rearrangements (MCRs), and 42 couples with MCRs combined with MCPs who underwent IVF/ICSI treatment at Peking University Third Hospital from 2015 to 2021. The semen quality, embryological outcomes, and clinical outcomes of different groups stratified by karyotypes were compared.

Results

For couples undergoing IVF, male inv(9) was associated with a significantly lower sperm viability rate (29.41% vs 34.49%, P = 0.030), a lower progressive motility rate (25.13% vs 30.50%, P = 0.013), and a lower normal fertilization rate (52.41% vs 59.84%, P = 0.014). Male 9qh + was related to a lower sperm viability rate (27.56% vs 34.49%, P = 0.028). No MCPs were observed to compromise clinical outcomes in couples undergoing IVF. For couples undergoing ICSI, no MCPs exhibited an association with poorer semen quality and embryological outcomes. However, Yqh + and DGpstk+ were found to be significantly correlated with an increased likelihood of preterm birth (23.3% vs 9.2%, P = 0.003; 20.0% vs 9.2%, P = 0.041, respectively). In couples with MCRs, the presence of MCPs significantly reduced the sperm viability rate (19.99% vs 30.97%, P = 0.017) and progressive motility rate (8.07% vs 27.85%, P = 0.018).

Conclusion

Our study provides detailed evidence for the impacts of various MCPs on IVF/ICSI outcomes, reveals the complexity and heterogeneity of these impacts, and highlights the adverse effects of male inv(9).
Neural stochastic agent‐based limit order book simulation with neural point process and diffusion probabilistic model
Authors: Shi Zijian , Cartlidge John
Published: April 2024

Modern financial exchanges use an electronic limit order book (LOB) to store bid and ask orders for a specific financial asset. As the most fine‐grained information depicting the demand and supply of an asset, LOB data are essential in understanding market dynamics. Therefore, realistic LOB simulations offer a valuable methodology for explaining the empirical properties of markets. Mainstream simulation models include agent‐based models (ABMs) and stochastic models (SMs). However, ABMs tend not to be grounded on real historical data, whereas SMs tend not to enable dynamic agent‐interaction. More recently, deep generative approaches have been successfully implemented to tackle these issues, whereas its black‐box essence hampers the explainability and transparency of the system. To overcome these limitations, we propose a novel hybrid neural stochastic agent‐based model (NS‐ABM) for LOB simulation that incorporates a neural stochastic trader in agent‐based simulation, characterised by (1) representing the aggregation of market events' logic by a neural stochastic background trader that is pre‐trained on historical LOB data through a neural point process model; (2) learning the complex distribution for order‐related attributes conditioned on various market indicators through a non‐parametric diffusion probabilistic model; and (3) embedding the background trader in a multi‐agent simulation platform to enable interaction with other strategic trading agents. We instantiate this hybrid NS‐ABM model using the ABIDES platform. We first run the background trader in isolation and show that the simulated LOB can recreate a comprehensive list of stylised facts that demonstrate realistic market behaviour. We then introduce a population of ‘trend’ and ‘value’ trading agents, which interact with the background trader. We show that the stylised facts remain and we demonstrate order flow impact and financial herding behaviours that are in accordance with empirical observations of real markets.
When one tool is not enough: An integrative psychotherapeutic approach to treating complex PTSD
Authors: Horesh Danny , Lahav Yael
Published: April 2024

Complex posttraumatic stress disorder (CPTSD) is a term representing the psychopathological implications of exposure to chronic, inter‐personal trauma. These include the main symptoms of PTSD, as well as changes in identity, emotion regulation, and inter‐personal relationships. Self‐harm and dissociation (i.e., disintegration of mental processes) are also quite common in CPTSD. Considering this complex and often severe clinical picture, mental health professionals often find it difficult to effectively treat CPTSD. In this paper, we present an integrative approach to the treatment of CPTSD based on a combination of techniques from several psychotherapy approaches. The case described here illustrates the need for therapeutic flexibility and eclecticism when treating individuals exposed to chronic trauma. We show the advantages of flexible therapeutic attunement, which enables the therapist to respond to the changing need of the patient, as well as her fluid clinical picture and symptom manifestation. The case also illustrates how interventions taken from psychodynamic therapy, Dialectical behavior therapy, and Eye Movement Desensitization and Reprocessing may be applicable in various stages of treatment, alleviating the patient's distress in several psychological and physical domains.
A general inductive approach to characterize transdiagnostic experiences of emptiness
Authors: Hudson Chloe C. , Ferguson IreLee , Fan Kailyn , Björgvinsson Thröstur , Beard Courtney
Published: April 2024

Background

Despite the pervasiveness of patient‐reported emptiness and the high burden it carries, emptiness is poorly understood. In the current study, we used a general inductive approach to examine experiences with emptiness in a diagnostically diverse sample of treatment‐seeking patients with severe and acute psychopathology. As a secondary aim, we also examined whether identified themes differed among patients with a primary diagnosis of borderline personality disorder or major depressive disorder.

Method

Participants (n = 150) ranged from 18 to 69 years old (M = 33.15, SD = 12.41; 79.3% non‐Hispanic White; 57.3% females). All patients completed the borderline personality disorder module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Personality Disorders and the Mini International Neuropsychiatric Interview. Interviewers documented patients' responses to follow‐up questions. Patients were included in the study if they endorsed chronic feelings of emptiness and elaborations were documented.

Results

We identified 10 themes associated with patient‐reported emptiness: (1) purposeless, (2) lack of connection, (3) numbness, (4) self‐deprecation, (5) lack of identity, (6) lack of motivation, (7) hopelessness, (8) lack of pleasure, (9) physical sensation, and (10) dissociation. Themes were consistent across diagnostic status, with one exception: patients with borderline personality disorder were more likely to report that emptiness was associated with dissociation relative to patients with major depressive disorder.

Conclusion

Our results suggest that emptiness may reflect a multifaceted and transdiagnostic construct. Identified themes may help to support the assessment of emptiness and can be used to guide individualized treatments.
Trends in functional outcome measures in orthopedic oncology
Authors: Le David , Martin Kelsey , Clark Sean C. , Ruso Devyn , Hoyen Alex , Hunter Krystal , Kim Tae Won B.
Published: April 2024

The purpose of this study was to identify trends in the use of functional outcome measures within orthopedic oncology. The search engine, PubMed, was reviewed for all articles over an 11‐year period from 2011 to 2021 from five major journals that publish in the field of orthopedic oncology. The functional outcome measures used in the articles were recorded along with study date, study design, clinical topic/pathology, and level of evidence. Out of 5968 musculoskeletal tumor‐focused articles reviewed, 293 (4.9%) included at least one outcome measure. A total of 28 different outcome tools were identified. The most popular were Musculoskeletal Tumor Society (MSTS) score (61.1%) and Toronto Extremity Salvage (TESS) score (14.0%), followed by 36‐Item Short Form Survey (SF‐36) (4.1%) and Patient‐Reported Outcomes Measurement Information System (PROMIS) (3.8%). The use of MSTS scores decreased by 0.7% each year, whereas PROMIS increased by 1.2% each year. Seventy‐four articles used more than one outcome measure. Of these 74 articles, 61 had the MSTS as one of the outcome measures. Orthopedic oncology utilizes functional outcome measures less commonly in comparison to other orthopedic subspecialties. However, this may be due in large part to orthopedic oncologists putting more emphasis on outcomes such as local recurrence, implant failure, and mortality. MSTS score is the most widely used functional outcome measure, but the utilization of PROMIS has increased recently, and could be the next step in evaluating outcomes in orthopedic oncology as it is patient‐derived rather than physician‐derived.
Simultaneous determination of folic acid photolysis products and oxidized guanine derivatives in plasma by liquid chromatography‐tandem mass spectrometry
Authors: Li Juan , Hu Wenchao , Liu Mengxue , Tian Yingqi , He Manni , Liu Hongmin
Published: April 2024

Folic acid (FA) is easily photodegraded to yield 6‐formylpterin and pterin‐6‐carboxylic acid, which can generate reactive oxygen species and result in the formation of oxidized guanine derivatives such as 8‐hydroxy‐2′‐deoxyguanosine and 8‐hydroxy‐guanosine. In this study, we developed a simple, rapid, and sensitive liquid chromatography‐tandem mass spectrometry strategy for the simultaneous determination of FA photolysis products and oxidized guanine derivatives in plasma samples. Chromatographic separation was performed on a Waters HSS T3 column (2.1 × 100 mm, 5.0 μm) with gradient elution at a flow rate of 0.25 mL/min. Plasma samples were first pretreated with 1% formic acid, followed by protein precipitation with methanol. The developed method showed good linear relationships between 1 and 2000 ng/mL (r2 > 0.99). The intra‐ and inter‐day precisions ranged from 2.6% to 7.5% and from 2.5% to 6.5%, respectively. Recoveries of the analytes were between 75.4% and 112.4% with the relative standard deviation < 9.1%. Finally, the method was applied to quantify FA photolysis products and oxidized guanine derivatives in rats with light and non‐light conditions.
All‐inside endoscopic semiautomatic running locked stitch technique shows favourable outcomes for acute Achilles tendon ruptures
Authors: Wei Shijun , Li Qing , Wu Helin , Kong Changwang , Xu Feng , Cai Xianhua
Published: April 2024

Purpose

The safety and reliability of endoscopic Achilles tendon rupture repair are still concerning aspects. This study's aim is to evaluate an all‐inside endoscopic semiautomatic running locked stitch (Endo‐SARLS) technique.

Methods

Forty cases with acute Achilles tendon rupture were treated with the all‐inside Endo‐SARLS technique between 2020 and 2021. Under endoscopic control, the proximal tendon stumps were stitched with the running locked method using a semiautomatic flexible suture passer. The threads of the high‐strength suture were grasped through the paratenon subspace and then fixed into calcaneal insertion with a knotless anchor. Magnetic resonance imaging (MRI), surgical time and complications were assessed. Achilles Tendon Total Rupture Score (ATRS), Achilles Tendon Resting Angle (ATRA) and Heel Rise Height Scale (HRHS) were utilised to evaluate final outcomes.

Results

The average follow‐up time was 25.4 ± 0.4 (range: 24–32) months. Appropriate tendon regeneration was observed on MRI after 12 months. At the final follow‐up, the median value of ATRS score was 95 (interquartile range: 94, 98). Furthermore, there is no significant difference between the injured and contralateral side in the average ATRA (18.2 ± 1.8 vs. 18.3 ± 1.9°, ns) and median value of HRHS [14.5 (13.3, 15.5) vs. 14.8 (13.5, 15.6) cm, ns]. No infection and nerve injuries were encountered. Thirty‐nine patients reported that they resumed casual sports activity after 6 months. One patient had a slight anchor cut‐out, due to an addition injury, which was removed after 5 months.

Conclusions

An all‐inside Endo‐SARLS technique showed promising clinical results for acute Achilles tendon ruptures. This procedure reduces the risk of sural nerve injuries while establishing a reliable connection between the tendon stumps.

Level of Evidence

Level IV.
Photoaffinity labeling coupled to MS to identify peptide biological partners: Secondary reactions, for better or for worse?
Authors: Walrant Astrid , Sachon Emmanuelle
Published: April 2024

Affinity photolabeling is a smart method to study noncovalent and transient interactions and provide a submolecular picture of the contacts between interacting partners. In this review, we will focus on the identification of peptide partners using photoaffinity labeling coupled to mass spectrometry in different contexts such as in vitro with a purified potential partner, in model systems such as model membranes, and with live cells using both targeted and nontargeted proteomics studies. Different biological partners will be described, among which glycoconjugates, oligonucleotides, peptides, proteins, and lipids, with the photoreactive label inserted either on the peptide of interest or on the potential partner. Particular attention will be paid to the observation and characterization of specific rearrangements following the photolabeling reaction, which can help characterize photoadducts and provide a better understanding of the interacting systems and environment.
Simulated cost‐effectiveness of a novel precision‐guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy
Authors: Alizadeh Elmar R. , Dervieux Thierry , Vermeire Severine , Dubinsky Marla , D'Haens Geert , Laharie David , Shim Andrew , Vaughn Byron P.
Published: April 2024

Background

Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision‐guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost‐effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS).

Methods

We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4‐week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real‐world clinical PK data and interventional clinical trial patient‐level data. All other transition probabilities were derived from published randomized clinical trials and cost‐effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost‐effectiveness ratios (ICERs). The robustness of results was assessed via one‐way sensitivity, scenario, and probabilistic sensitivity analyses (PSA).

Results

PGD was the cost‐effective IFX dosing strategy with an ICER of 122,932 $ per quality‐adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One‐way sensitivity analysis demonstrated that the cost‐effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results.

Conclusions

PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost‐effective under conservative assumptions.
An evaluation of physical medicine and rehabilitation accredited sports medicine fellowship websites
Authors: Khalil Michael , Ho Elver S. , Zweig Sophia , Agarwal Sanjeev
Published: April 2024

Background

Due to the virtual format of fellowship applications, prospective physical medicine and rehabilitation (PM&R) sports medicine fellowship applicants commonly rely upon fellowship website content to make decisions about applications. Studies have shown that information available to fellowship applicants on program websites is inadequate, and there is no standard for important components of sports medicine fellowship websites.

Objective

To determine what sports medicine fellowship program features PM&R residents, fellows, and attending physicians consider the most important to be listed on fellowship websites, as well as to assess the scope of information available on fellowship websites.

Design

We developed a 30‐item list of criteria that fell into categories of general information, fellowship education, recruitment, experience, and academic research. Survey participants were asked to rank the importance of those various items. We then assessed the 21 PM&R accredited sports medicine fellowship websites for the presence of these criteria.

Participants

Ninety‐six survey respondents composed of PM&R residents, current sports medicine fellows, and attendings.

Interventions

Not applicable.

Main Outcome Measure(s)

Not applicable.

Results

Items ranked as most important were those in the categories of general information, fellowship experience, and fellowship recruitment. The most valued items were program location, program coordinator contact information, program length, specific requirements for applying, number of positions, types of procedures taught, and specific sites covered. Academic research items were ranked as least important.

Conclusions

Survey respondents identified many fellowship website items as important factors when applying to programs. Many of these items were not listed on fellowship websites, suggesting that adding these criteria to fellowship sites might benefit applicants. Our findings can be used to develop standardized criteria for important components of sports medicine fellowship websites to improve the application and recruitment process.
Molecular Basis of the Curative Effects of Turkish Gall Extracts on Periodontitis
Authors: Luo Xiaojie , Zha Siqin , Su Xu , Wang Yue , Zhang Miao , Chen Xiaotao
Published: April 2024

We explored the mechanism whereby Turkish gall extracts prevent and effectively cure periodontitis. Main bioactive components were obtained from previous reports and targets were screened using TCMSP, PubChem, SwissTargetPrediction, and Drugbank databases. Chronic periodontitis targets were retrieved from OMIM, GeneCards, and DisGeNET databases. Intersectional targets of Turkish galls and periodontitis were obtained using Venn analysis. String databases were used to construct a protein–protein interaction network of common targets. R language was used for GO and KEGG enrichment analyses of common targets. Molecular docking analysis confirmed Turkish gall extract effectiveness for periodontitis treatment, which was verified in vitro and inhibited MAPK1, MAPK3 and SRC expression. We predicted 759 possible target genes. Among 2059 identified periodontitis genes, 205 overlapped with those in methanolic Turkish gall extract. Key targets included JUN, tumor protein 53, MAPK1, MAPK3, STAT3, RELA, and SRC. GO analysis showed that common targets were mainly involved in processes such as oxidative stress. KEGG analysis indicated that common targets were enriched in 163 pathways. Molecular docking analysis showed that 1,2,3,6‐tetra‐O‐galloyl‐β‐D‐glucose, 1,3,6‐tri‐O‐galloyl‐β‐D‐glucose and 1,2,3,4,6‐penta‐O‐galloyl‐β‐D‐glucose were strongly associated with MAPK1, MAPK3, and SRC. Turkish gall extract reduced inflammation and targets expression in vitro, providing a reference for drug development for periodontitis.
What next? Some practical suggestions for future studies on fence ecology
Authors: Buton Caryl , Kaldonski Nicolas , Nowicki François , Saint‐Andrieux Christine
Published: April 2024

Practical gaps in knowledge of fence ecology or its specific requirements still exist despite numerous recommendations scattered throughout various articles. We recently carried out two different studies on fences in a French context whose results corroborate this observation, and highlight the need to synthetise and prioritise scientific and technical research. The first study was an exploratory research project on escape devices used to allow ungulates to exit fenced transport infrastructure right‐of‐way. The second study entailed drafting a guide on the mitigation of the fence's ecological impacts, using solar energy plants as a case study. Both were based on different types of information gathering, ranging from bibliographical research to interviews with governments officials, operating companies, engineering offices, naturalists and hunters' associations.

Based on the similarities between these two studies, the urgency of certain needs, and the clear potential for these approaches to extend beyond France's borders, we have identified two key categories for future actions. The first category is a series of six research priorities: Diversifying monitoring of exclusion fencing; Developing practice‐oriented fence mapping tools; Further studying the impact of fencing on animal vehicle collisions; Considering animal behaviour in monitoring protocol; Ex‐situ testing of devices' effectiveness; and Studying large‐scale effects of fencing. The second category comprises six method recommendations: Accurately documenting fences; Early planning of scientific monitoring; Contextualising fencing requirements; Defining effectiveness goals and criteria; Taking advantage of opportunistic Animal‐Fence Event observations; and Developing artificial intelligence and computer vision to map fences. All these items are supported by examples drawn from one study or the other.

Our conclusions indicate that, in the context of major expansion of fences, such recommendations must be integrated at all stages of development work. If this is not implemented, the free movement of animal species will not be adequately protected and the erosion of biodiversity will be further exacerbated.
On Basic Feasible Functionals and the Interpretation Method
Authors: Baillot Patrick , Dal Lago Ugo , Kop Cynthia , Vale Deivid
Published: April 2024

The class of basic feasible functionals ($$\texttt{BFF}$$
BFF
) is the analog of $$\texttt{FP}$$
FP
(polynomial time functions) for type-2 functionals, that is, functionals that can take (first-order) functions as arguments. $$\texttt{BFF}$$
BFF
can be defined through Oracle Turing machines with running time bounded by second-order polynomials. On the other hand, higher-order term rewriting provides an elegant formalism for expressing higher-order computation. We address the problem of characterizing $$\texttt{BFF}$$
BFF
by higher-order term rewriting. Various kinds of interpretations for first-order term rewriting have been introduced in the literature for proving termination and characterizing (first-order) complexity classes. In this paper, we consider a recently introduced notion of cost–size interpretations for higher-order term rewriting and see definitions as ways of computing functionals. We then prove that the class of functionals represented by higher-order terms admitting a certain kind of cost–size interpretation is exactly $$\texttt{BFF}$$
BFF
.
Craig Interpolation for Decidable First-Order Fragments
Authors: ten Cate Balder , Comer Jesse
Published: April 2024

We show that the guarded-negation fragment (GNFO) is, in a precise sense, the smallest extension of the guarded fragment (GFO) with Craig interpolation. In contrast, we show that the smallest extension of the two-variable fragment ($$\textrm{FO}^2 $$

FO
2

), and of the forward fragment (FF) with Craig interpolation, is full first-order logic. Similarly, we also show that all extensions of $$\textrm{FO}^2 $$

FO
2

and of the fluted fragment (FL) with Craig interpolation are undecidable.
Towards Reliable SQL Synthesis: Fuzzing-Based Evaluation and Disambiguation
Authors: Brancas Ricardo , Terra-Neves Miguel , Ventura Miguel , Manquinho Vasco , Martins Ruben
Published: April 2024

In recent years, more people have seen their work depend on data manipulation tasks. However, many of these users do not have the background in programming required to write complex programs, particularly SQL queries. One way of helping these users is automatically synthesizing the SQL query given a small set of examples. Several program synthesizers for SQL have been recently proposed, but they do not leverage multicore architectures.

This paper proposes Cubes, a parallel program synthesizer for the domain of SQL queries using input-output examples. Since input-output examples are an under-specification of the desired SQL query, sometimes, the synthesized query does not match the user’s intent. Cubes incorporates a new disambiguation procedure based on fuzzing techniques that interacts with the user and increases the confidence that the returned query matches the user intent. We perform an extensive evaluation on around 4000 SQL queries from different domains. Experimental results show that our parallel approach can scale up to 16 processes with super-linear speedups for many hard instances, and that our disambiguation approach is critical to achieving an accuracy of around 60%, significantly larger than other SQL synthesizers.
Probabilistic Runtime Enforcement of Executable BPMN Processes
Authors: Falcone Yliès , Salaün Gwen , Zuo Ahang
Published: April 2024

A business process is a collection of structured tasks corresponding to a service or a product. Business processes do not execute once and for all, but are executed multiple times resulting in multiple instances. In this context, it is particularly difficult to ensure correctness and efficiency of the multiple executions of a process. In this paper, we propose to rely on Probabilistic Model Checking (PMC) to automatically verify that multiple executions of a process respect some specific probabilistic property. This approach applies at runtime, thus the evaluation of the property is periodically verified and the corresponding results updated. However, we go beyond runtime PMC for BPMN, since we propose runtime enforcement techniques to keep executing the process while avoiding the violation of the property. To do so, our approach combines monitoring techniques, computation of probabilistic models, PMC, and runtime enforcement techniques. The approach has been implemented as a toolchain and has been validated on several realistic BPMN processes.
Refinement Verification of OS Services based on a Verified Preemptive Microkernel
Authors: Li Ximeng , Chen Shanyan , Guan Yong , Zhang Qianying , Wang Guohui , Shi Zhiping
Published: April 2024

An OS microkernel can be extended by implementing services upon it. A service could introduce an object that references a kernel object, and implement a group of functions that invokes the functions for manipulating the kernel object. We consider the scenario where the microkernel has been verified with machine-checkable proofs, while the services remain to be verified. Moreover, the verification of the microkernel is not performed with the verification of subsequent extension in mind. We address the problem of how to build sufficiently on the verification results for the microkernel, in achieving the verification of the services. Our methodology consists of enhancements to the verification framework for the microkernel, and the design of invariants for establishing the connection between the service-level objects and the kernel-level objects. Using the methodology, we have conducted a substantial formal verification of a group of services extending the inter-task communication functionalities of the preemptive microkernel $$\mu \!\!\text{ C }\!\!\text{/ }\!\!\!\text{ OS-II }$$

μ

C

/

OS-II

. Our verification uncovers dormant bugs and provides a level of correctness assurance for the services that is above what is achievable through extensive testing.
Global centers of a family of cubic systems
Authors: Appis Raul Felipe , Llibre Jaume
Published: April 2024

Consider the family of polynomial differential systems of degree 3, or simply cubic systems $$ x' = y, \quad y' = -x + a_1 x^2 + a_2 xy + a_3 y^2 + a_4 x^3 + a_5 x^2 y + a_6 xy^2 + a_7 y^3, $$

x
′

=
y
,

y
′

=
-
x
+

a
1

x
2

+

a
2

x
y
+

a
3

y
2

+

a
4

x
3

+

a
5

x
2

y
+

a
6

x

y
2

+

a
7

y
3

,

in the plane $$\mathbb {R}^2$$

R

2

. An equilibrium point $$(x_0,y_0)$$

(

x
0

,

y
0

)

of a planar differential system is a center if there is a neighborhood $$\mathcal {U}$$
U
of $$(x_0,y_0)$$

(

x
0

,

y
0

)

such that $$\mathcal {U} \backslash \{(x_0,y_0)\}$$

U
\
{

(

x
0

,

y
0

)

}

is filled with periodic orbits. When $$\mathbb {R}^2\setminus \{(x_0,y_0)\}$$

R

2

\

{

(

x
0

,

y
0

)

}

is filled with periodic orbits, then the center is a global center. For this family of cubic systems Lloyd and Pearson characterized in Lloyd and Pearson (Comput Math Appl 60:2797–2805, 2010) when the origin of coordinates is a center. We classify which of these centers are global centers.
CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to prevent DNA hypermethylation and ensure normal transcription in growing oocytes
Authors: Ren Peipei , Tong Xiaomei , Li Junjian , Jiang Huifang , Liu Siya , Li Xiang , Lai Mengru , Yang Weijie , Rong Yan , Zhang Yingyi , Jin Jiamin , Ma Yerong , Pan Weiwei , Fan Heng-Yu , Zhang Songying , Zhang Yin-Li
Published: April 2024

The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.
Bilayer surrogate brain response under various blast loading conditions
Authors: Norris C. , Arnold B. , Wilkes J. , Squibb C. , Nelson A. J. , Schwenker H. , Mesisca J. , Vossenberg A. , VandeVord P. J.
Published: April 2024

Variations in the experimental constraints applied within blast simulations can result in dramatically different measured biomechanical responses. Ultimately, this limits the comparison of data between research groups and leads to further inquisitions about the “correct” biomechanics experienced in blast environments. A novel bilayer surrogate brain was exposed to blast waves generated from advanced blast simulators (ABSs) where detonation source, boundary conditions, and ABS geometry were varied. The surrogate was comprised of Sylgard 527 (1:1) as a gray matter simulant and Sylgard 527 (1:1.2) as a white matter simulant. The intracranial pressure response of this surrogate brain was measured in the frontal region under primary blast loading while suspended in a polyurethane spherical shell with 5 mm thickness and filled with water to represent the cerebrospinal fluid. Outcomes of this work discuss considerations for future experimental designs and aim to address sources of variability confounding interpretation of biomechanical responses.
The Fourier spectrum and sumset type problems
Authors: Fraser Jonathan M.
Published: April 2024

We introduce and study the Fourier spectrum which is a continuously parametrised family of dimensions living between the Fourier dimension and the Hausdorff dimension for both sets and measures. We establish some fundamental theory and motivate the concept via several applications, especially to sumset type problems. For example, we study dimensions of convolutions and sumsets, and solve the distance set problem for sets satisfying certain Fourier analytic conditions.