bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on multi-objective optimization torque distribution strategy for distributed drive electric vehicles based on dung beetle optimizer
Authors: Li Wenzhe , Zhang Yong , Qin Yanbin , Zhao Fengkui , Wan Maosong , Gao Feng
Published: December 2024

Distributed drive electric vehicles (DDEVs), characterized by compact structure, efficient transmission, and flexible control, have gradually become the mainstream in the development of new energy electric vehicles. This study focuses on DDEVs and employs a hierarchical control strategy. At the upper level, a sliding mode controller is used for vehicle yaw stability control, while torque distribution is performed at the lower level. Addressing the shortcomings of conventional average and load-based distribution methods in terms of energy consumption, this paper proposes a multi-objective torque distribution strategy that optimizes tire load ratio, torque deviation, and motor energy consumption. The strategy integrates objective functions using weighting coefficients and imposes constraints based on road adhesion and motor output capabilities. To tackle this optimization problem, the Dung Beetle Optimizer (DBO) algorithm is introduced, known for its efficient global search capabilities and adaptability. By applying the DBO algorithm, the optimal torque distribution scheme under constraints is determined. Finally, through joint simulations using Carsim and Matlab/Simulink, comparative experiments are conducted under different conditions to evaluate the simulation results of average distribution, load-based distribution, and DBO multi-objective optimization distribution. The experimental findings demonstrate that the proposed multi-objective torque distribution strategy effectively balances tire load ratio, torque deviation, and motor energy consumption, thereby enhancing the overall performance of distributed drive electric vehicles.
Optical wave packet compression using counterpropagating Scorer beams
Authors: Zhong Wei-Ping , Belić Milivoj , Yang Zheng-Ping
Published: December 2024

We investigate the diffractive paraxial wave equation with an external potential, utilizing self-similarity and variable separation methods. The exact solution to this evolution equation, expressed through Scorer functions, gives rise to the new Scorer beams. We explore the dynamics of counterpropagating Scorer beams, as promising optical wave packets, focusing on their compression behavior. The Scorer beams are characterized by two key parameters: the attenuation factor and the initial pulse width. By appropriately adjusting these parameters, significant beam compression can be achieved. Specifically, increasing the attenuation factor enhances compression and raises pulse amplitude, while reducing the initial pulse width further amplifies these effects. Along the way, we observe interesting interference patterns of the counterpropagating Scorer beams that have never been seen before. This study introduces a novel approach to beam compression and opens new possibilities for practical applications of Scorer beams.
Identifying child growth effects of elevated pollution levels during pregnancy
Authors: Heft-Neal Sam , Philipp Heger Martin , Rathi Vaibhav , Burke Marshall
Published: December 2024

Poor air quality is known to be one of the leading contributors to poor child health globally, and a wealth of evidence has linked pollution exposure during pregnancy to adverse birth and early-life outcomes. While there is some evidence pollution exposure during pregnancy is associated with slowed child growth, this evidence is largely limited to empirical settings in which it is difficult to disentangle the role of pollution from other co-varying factors. Here we rely on quasi-random variation in pollution conditions induced by thermal inversions to estimate the impact of pollution spikes during pregnancy on childhood stunting. We find that thermal inversions during pregnancy worsen air quality and increase the likelihood of childhood stunting, but only in places with poor baseline air quality and particularly for younger children and in lower-wealth communities. Our estimates imply that a 1  µg m−3 increase in average PM2.5 concentration during pregnancy increases the probability of stunting by an average of 4.1 percentage points (95% CI: 0.2–8.0). This translates to an 11.2% increase (95% CI: 0.6%–21.9%) in stunting risk from the sample baseline of 37% children stunted. Our results suggest that policies that limit baseline daily PM2.5 levels, particularly during seasons when thermal inversions are more frequent, have potential to generate meaningful improvements in long-run child outcomes.
High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myeloid leukemia
Authors: Rudzinska-Radecka M , Turos-Korgul L , Mukherjee D , Podszywalow-Bartnicka P , Piwocka K , Guzowski J
Published: December 2024

Leukemic microenvironment has been recognized as a factor that strongly supports the mechanisms of resistance. Therefore, targeting the microenvironment is currently one of the major directions in drug development and preclinical studies in leukemia. Despite the variety of available leukemia 3D culture models, the reproducible generation of miniaturized leukemic microenvironments, suitable for high-throughput drug testing, has remained a challenge. Here, we use droplet microfluidics to generate tens of thousands of highly monodisperse leukemic-bone marrow microenvironments within minutes. We employ gelatin methacryloyl (GelMA) as a model extracellular matrix (ECM) and tune the concentration of the biopolymer, check the impact of other components of the ECM (hyaluronic acid), cell concentration and the ratio of leukemic cells to bone marrow cells within the microbeads to establish the optimal conditions for microtissue formation. We administer model kinase inhibitor, imatinib, at various concentrations to the encapsulated leukemic microtissues, and, via comparing mono- and co-culture conditions (cancer alone vs cancer-stroma), we find that the stroma–leukemia crosstalk systematically protects the encapsulated cells against the drug-induced cytotoxicity. With that we demonstrate that our system mimics the physiological stroma-dependent protection. We discuss applicability of our model to (i) studying the role of direct- or close-contact interactions between the leukemia and bone marrow cells embedded in microscale 3D ECM on the stroma-mediated protection, and (ii) high-throughput screening of anti-cancer therapeutics in personalized leukemia therapies.
Effect of scanning strategies on microstructure and wear behavior of Inconel 718 fabricated by selective laser melting
Authors: Hu Zhiqiang , Song Bin , Zhang Donghui
Published: December 2024

To study the effect of the rotating angle on microstructure and wear properties of Inconel 718 alloy manufactured by selective laser melting (SLM) technology, parts were fabricated with two different scanning strategies (67°, 90°). The results revealed that the Inconel 718 produced by SLM with a 67° rotating angle exhibits higher surface roughness and a distinct cubic texture {100} <001>. Additionally, rotation angle of 90° will enhance grain coarsening and weaken texture strength. The influence of rotation angles on the hardness of SLMed Inconel 718 is negligible at room temperature. The wear resistance of SLMed Inconel 718 is superior at high temperatures compared to room temperature. The wear mechanisms of SLMed Inconel 718 at room temperature and high temperature are primarily governed by abrasive wear and adhesive wear, and oxidation wear, respectively. The favorable wear properties observed at the 67° rotating angle can be attributed mainly to the fine cellular structure and the triboxide layer.
Mixing thermal coherent states for precision and range enhancement in quantum thermometry
Authors: Ullah Asghar , Tahir Naseem M , Müstecaplıoğlu Özgür E
Published: December 2024

The unavoidable interaction between thermal environments and quantum systems typically leads to the degradation of quantum coherence, which can be fought against by reservoir engineering. We propose the realization of a special mixture of thermal coherent states by coupling a thermal bath with a two-level system (TLS) that is longitudinally coupled to a resonator. We find that the state of the resonator is a special mixture of two oppositely displaced thermal coherent states, whereas the TLS remains thermal. This observation is verified by evaluating the second-order correlation coefficient for the resonator state. Moreover, we reveal the potential benefits of employing the mixture of thermal coherent states of the resonator in quantum thermometry. In this context, the resonator functions as a probe to measure the unknown temperature of a bath mediated by a TLS, strategically bridging the connection between the two. Our results show that the use of an ancillary-assisted probe may enhance the precision and broaden the applicable temperature range.
A student-led approach to completion of the Practice Advancement Initiative 2030 self-assessment tool with a state affiliate in North Dakota
Authors: Johnson Madelyn J , Afifi Habiba , Meyer Amanda , Loy Maari
Published: November 2024

Purpose

To efficiently complete Practice Advancement Initiative (PAI) 2030 self-assessments, students aimed to overcome completion barriers and collect data to identify areas for improvement with pharmacy practice in the state of North Dakota.

Pharmacy departments from hospitals and health systems face challenges when completing the self-assessment tool, and creativity must be kindled to develop an appropriate approach. Over the course of a 5-week advanced pharmacy practice experience rotation, 2 students generated an efficient, personal, and novel approach to completing the PAI 2030 self-assessment tool with pharmacy leaders across the state.

Conclusion

The novel student-led approach achieved a completion rate greater than the goal suggested by the American Society of Health-System Pharmacists while providing the students with learning and networking opportunities. As a result, pharmacy leaders have baseline PAI 2030 self-assessment data for 26 hospitals across North Dakota, which can be used for further analysis and application.
Identification and Characterization of Acidic Degradation Products of Moxidectin Drug Substance Including Degradation Pathways Using LC, HRMS, and NMR
Authors: Huang Tyler C , Nisathar Ayesha , Rinaldi Frank
Published: December 2024

Background

Moxidectin is an active pharmaceutical ingredient (API) extensively used in various drug products within the pharmaceutical and animal health sectors. Despite its widespread use, the analytical methods prescribed by the United States Pharmacopeia (USP) and European Pharmacopoeia (EP, Ph. Eur.) exhibit significant limitations. These methods fail to adequately separate key impurities of (23Z)-moxidectin (EP impurity L) and 3,4-epoxy-moxidectin, potentially affecting the quality control, purity assessment, and safety of moxidectin-containing products.

Objective

The objective was to develop and validate an alternative, improved stability-indicating high-performance liquid chromatography (HPLC) method for the identification, assay, and quantification of related substances in the moxidectin drug substance, along with the analysis of its degradation pathways.

Methods

High-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) were employed to comprehensively examine moxidectin and its two degradation products under specified acidic conditions. The degradation products were isolated and identified using a range of analytical techniques, including HRMS, NMR, and other relevant methods.

Results

The epoxy derivative of moxidectin (relative retention time [RRT] = 1.2) was not identified under the studied acidic degradation conditions. HRMS data indicated that the degradant at RRT = 1.2 is an isomer of moxidectin, as it exhibited an identical molecular ion. Detailed NMR studies on moxidectin and its impurity at RRT-1.2 revealed differences in carbon and proton chemical shifts at positions C-22 and C-24, strongly supporting the identification of the structure as an oxime geometric isomer of moxidectin, i.e. (23Z)-moxidectin.

Conclusions

The findings revealed specific degradation products formed under acidic conditions, offering valuable insights into the chemical transformations of moxidectin. This information is crucial for assessing the drug’s stability profile and ensuring the quality and safety of moxidectin-containing products.

Highlights

The HPLC method developed in this study significantly improves on existing USP/EP methods with regard to a separation of key impurities of (23Z)-moxidectin and 3,4-epoxy-moxidectin, offering robust performance for routine analysis of bulk moxidectin API batches and stability samples in quality control (QC) laboratories.
Optical Density Assay to Determine the Sensitivity of Globisporangium and Pythium Isolates to Mefenoxam
Authors: Ilyas Umbrin , du Toit Lindsey J. , McDonald Mary Ruth
Published: December 2024

Several species of Globisporangium and Pythium cause cavity spot of carrot. Disease management in conventional production relies primarily on application of the fungicide mefenoxam. Growers’ reports in Ontario, Canada, of severe cavity spot, even when using mefenoxam applications, suggest that mefenoxam resistance may be prevalent in pathogen populations in this region. The objectives of the study were to develop a rapid and accurate optical density (OD) assay to assess mefenoxam sensitivity of 188 isolates of Globisporangium and Pythium species collected from 13 carrot fields in Ontario from 2020 to 2023. The isolates belonged to seven species: G. intermedium, G. irregulare, G. rostratifingens, G. sylvaticum, G. ultimum, G. violae, and P. sulcatum. The OD was measured at 600 nm in broth amended with different concentrations of mefenoxam, with OD readings at nine positions per well in a 96-well plate. The OD assay was validated by comparing half maximal effective concentration values with a standard fungicide-amended agar medium assay using 20 representative isolates. There was a significant linear relationship ( R2 = 0.97, P < 0.0001) between the two assays. Of the 188 isolates tested, 24% exhibited <60% inhibition of mycelial growth at 5 μg ml–1 mefenoxam, 50% were inhibited by >60% at 5 μg ml–1, 19% were inhibited by >60% at 1 μg ml–1, and 7% were inhibited by >60% even at 0.1 μg ml–1. The OD assay proved to be efficient, rapid, and accurate for monitoring the mefenoxam sensitivity of these oomycetes.

[Formula: see text] Copyright © 2025 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Depletion of ELMOD3 inhibits the growth and migration of gastric cancer cells by disrupting the β‐catenin signaling and the F‐actin cytoskeleton
Authors: Guo Pengli , Xu Chentong , Zhang Xuan , Feng Jinqiu , Lou Yaxin , Ye Shufang , Lv Ping , Zhu Bin , Chen Yingyu
Published: December 2024

ELMOD3 (encoding ELMO domain containing 3) is a causative gene associated with human autosomal dominant nonsyndromic and progressive hearing loss. However, the role of ELMOD3 in the occurrence and development of tumors remains unknown. Herein, we observed that inactivation of ELMOD3 in gastric cancer cells significantly inhibited their proliferation, migration, and invasion, and altered cell cycle progression. A xenograft tumor model showed that knockout of ELMOD3 suppressed the tumorigenicity of BGC823 gastric cancer cells in nude mice. Further investigation demonstrated that the ELMO domain of ELMOD3 interacts with β‐catenin, which increases the levels of β‐catenin, promoting downstream target gene expression. Deletion of ELMOD3 in gastric cells decreased the β‐catenin signaling, elevated E‐cadherin levels, suppressed RAF/MEK/ERK signal pathway, and disrupted the formation of F‐actin cytoskeleton. These results led us to propose that ELMOD3 may participate in multiple biological processes in promoting the tumorigenesis of gastric cancer. It exerts a positive role in the regulation of gastric cancer cell proliferation and progression. Thus, ELMOD3 was identified as a potential tumor target, which deserves further investigation.
Pediatric Medial Humeral Condyle Fractures: Classification, Treatment, and Outcomes
Authors: Orellana Kevin J. , Baghdadi Soroush , Buttrick Eliza , Värk Pille-Riin , Baldwin Keith , Shah Apurva S.
Published: December 2024

Background:

The purpose of this study was to develop and validate a classification system that describes the injury pattern of pediatric medial humeral condyle fractures and provide treatment guidelines.

Methods:

Patients less than 18 years old with medial humeral condyle fractures from 2012 to 2022 were identified. A classification system was developed based on fracture pattern and putative mechanism of injury. Type 1 fractures were characterized by a valgus/avulsion type injury while type 2 fractures were characterized by a vertical shear pattern. Each type was subdivided by amount of fragment displacement: (A) nondisplaced or minimally displaced (<2 mm) versus (B) displaced (>2 mm). Three attending orthopaedic surgeons evaluated and classified each patient’s fracture. Intrarater and inter-rater reliability was calculated with Kappa statistics.

Results:

Twenty-seven patients (16 males) with an mean age of 10.5 years were included. There were 4 type 1A, 17 type 1B, and 6 type 2B fractures with substantial agreement in inter-rater (ĸ=0.62, CI=0.45-0.78), and intrarater (mean ĸ=0.79, range=0.70-0.93) reliability analysis. Surgical treatment was performed in 25/27 patients; 4 patients underwent closed reduction percutaneous pinning (CRPP) and 21 underwent open reduction and internal fixation (ORIF). Ten patients required advanced imaging to assist in surgical decision making. Both nonoperative patients had type 1A fractures. Nearly one-fourth of patients (6/27, 22%) had some functional loss of motion and poor outcomes based on Flynn’s criteria, with a Fisher exact test revealing an increased risk of functional loss of motion in skeletally mature children (P=0.02). Two patients had complications including 1 nonunion after initial nonoperative management (type 1B) and 1 patient (type 2B) required manipulation under anesthesia for postoperative stiffness.

Conclusion:

Moderate to strong inter-rater and intrarater reliability was demonstrated with the proposed classification system. Type 1A fractures are amenable to nonoperative treatment while types 1B and 2B require surgical management. Skeletally mature patients may be at greater risk of motion loss following injury.

Level of Evidence:

Level IV—case series.
How Accurate and Effective Are Non–image-guided Thumb Basal Joint Injections When Performed by Experienced Fellowship-trained Hand Surgeons?
Authors: Sanchez-Navarro Gerardo E. , Rocks Madeline C. , Ayalon Omri , Paksima Nader , Hacquebord Jacques H. , Glickel Steven Z.
Published: December 2024

Background

Corticosteroid injections are widely used for treating thumb carpometacarpal (CMC) arthritis, yet the accuracy of non–image-guided injections in expert hands is uncertain, with prior studies reporting intraarticular placement in about 60% of thumbs when performed by physicians with different levels of training. Despite their common use, there is a need to assess both the accuracy and the short-term clinical efficacy of these injections, particularly when performed without image guidance by fellowship-trained hand surgeons.

Questions/purposes

(1) What is the accuracy of thumb CMC injections performed without image guidance by fellowship-trained hand surgeons in an office setting? (2) What is the short-term efficacy of thumb CMC injections performed without image guidance?

Methods

We prospectively enrolled 33 patients with a mean ± SD age of 63 ± 12 years, 76% (25) of whom were female, with symptoms of basal joint arthritis that persisted despite conservative treatment, and we administered 1.5-mL corticosteroid injections without image guidance. We used descriptive statistics to analyze the outcomes, which included VAS, QuickDASH (Q-DASH), and Thumb Disability Examination (TDX) scores. Minimum clinically important differences (MCIDs) were defined as 0.9 points for the VAS, 18 points for Q-DASH, and 17 points for TDX.

Results

Of the 33 injections analyzed, 79% (26) were intraarticular. At 6 weeks, patients reported a mean improvement of 22 points in QuickDASH, 24 points in TDX, and 4 points in VAS scores. Importantly, 73% (24 of 33), 55% (18 of 33), and 82% (27 of 33) of the patients achieved the MCID in the patient-reported outcomes, respectively, suggesting that even without image guidance, corticosteroid injections can provide effective short-term relief for thumb CMC arthritis.

Conclusion

We found that about 79% of injections were placed intraarticularly, which was comparable with the findings of previous studies using image guidance, and provided meaningful improvements in pain and function for 6 weeks. These findings suggest that for experienced fellowship-trained hand surgeons, non–image-guided injections remain a viable option. Future studies should explore long-term outcomes and the potential role of adjunctive treatments such as antiinflammatory medications and splinting to enhance patient care.

Level of Evidence

Level II, therapeutic study.
Menopause and Sexual Health: Hormones, Aging or Both?
Authors: Nappi Rossella E. , Cucinella Laura
Published: December 2024

Sexual health is multidimensional across the lifespan. At midlife, women may face challenges to sexuality, often requiring intervention. Menopause-related and age-related hormonal changes intermingle with common medical conditions and contribute to biological substrates less favorable to a healthy sexual response. Psychological, sociocultural, and relational factors modulate the impact of such changes positively or negatively, contributing to adaptation or manifestation of sexually related distress. A comprehensive diagnostic approach and multidimensional management are needed to address sexual symptoms due to both menopause and aging, individualizing non-pharmacological and pharmacological evidence-based treatment options according to personal goals and expectations in the woman/couple.
Human Papillomavirus Genotype Attribution and Integration in High-Grade Vaginal Intraepithelial Neoplasia
Authors: Shen Yuanming , Tang Sangsang , Zhou Yumei , Zhang Qiuxue , Chen Tingting , Li Jingnan , Wang Yu , Wan Xiaoyun , Lu Weiguo , Xu Junfen
Published: December 2024

Objective

The aim of the study was to investigate the distribution and association between human papillomavirus (HPV) genotypes and integration as well as their correlation with cervical lesions.

Methods

Two hundred seven patients diagnosed with high-grade vaginal intraepithelial neoplasia (HG-VaIN) were recruited from the Women's Hospital School of Medicine Zhejiang University between 2015 and 2021 and assayed for HPV genotyping. HPV integration sequencing analysis was conducted using tissues from 53 patients with HG-VaIN and 4 patients with invasive vaginal carcinoma (IVC), along with paired cervical lesion specimens.

Results

A total of 207 patients with HG-VaIN were categorized as having cervical lesions unrelated to HG-VaIN (group A, 71 patients, 34.30%) or cervical lesion-related HG-VaIN (group B, 136 patients, 65.70%). With an average follow-up of 42.19 months, 12 of 153 patients progressed to IVC and were all from group B. HPV16 infection and the presence of cervical lesions were the 2 main factors associated with disease progression, with cervical lesion coexistence being an independent factor. Compared with group A (5/20, 25%), group B (17/33, 51.52%) showed a higher rate of HPV integration, as demonstrated using HPV integration sequencing analysis, with HPV16 being the most integrated genotype (72.73%). The integration analysis of 4 patients with IVC paired with cervical lesion specimens showed that 3 of the 4 pairs exhibited the same HPV infection and integration sites, indicating a high degree of homology in HPV integration between cervical lesions and HG-VaIN-induced IVC.

Conclusions

Patients with HG-VaIN associated with cervical lesions exhibited a higher risk of malignant transformation, necessitating more proactive treatment approaches.
The incidence of hepatitis B reactivation in patients receiving ustekinumab: a systematic review and proportional meta-analysis
Authors: Alhalabi Marouf M. , Almokdad Rasha
Published: December 2024

Background:

This meta-analysis will evaluate the risk of hepatitis B reactivation in patients treated with ustekinumab for inflammatory bowel disease and psoriasis. We aim to determine the true incidence of this adverse event, reconcile discrepancies in reported reactivation rates, and elucidate the associated risk.

Methods:

We conducted a rigorous systematic review adhering to established guidelines. Major databases like MEDLINE, Google Scholar, CENTRAL, and ClinicalTrials.gov were searched. Studies involving patients with documented hepatitis B infection undergoing ustekinumab therapy were included. Patients receiving concurrent antiviral medications were excluded. To account for potential underreporting, studies without reactivation events or with sample sizes ≥3 were also considered by using generalized linear mixed models and Clopper–Pearson confidence intervals. This review was prospectively registered in PROSPERO (CRD42023418130).

Results:

We analyzed data from nine studies involving 104 hepatitis B virus (HBV)-infected patients. The pooled HBV reactivation (HBVr) incidence among hepatitis B surface antigen-positive patients was 10% [95% confidence interval (CI): 0–31%], with low heterogeneity (I
2 = 7.13%, τ
2 = 0.4) and a nonsignificant Q-statistic (Q = 5.38, P = 0.37). For the occult HBV-infected patients, the pooled HBVr incidence was 3% (95% CI: 0–11%), with no heterogeneity (I
2 = 0%, τ
2 = 0.0) and a nonsignificant Q-statistic (Q = 2.7, P = 0.61). The reactivation rates showed high consistency across studies, with no significant difference between the two groups.

Conclusions:

While our data suggest lower HBVr risk with ustekinumab, confirmation is needed due to limited sample size and retrospective design.
The Catatonia Quick Screen (CQS): A Rapid Screening Tool for Catatonia in Adult and Pediatric Populations
Authors: Luccarelli James , Kalinich Mark , Wilson Jo Ellen , Liu Jinyuan , Fuchs D. Catherine , Francis Andrew , Heckers Stephan , Fricchione Gregory , Smith Joshua Ryan
Published: November 2024

Introduction

Catatonia is a neuropsychiatric disorder marked by significant disturbances in motor, cognitive, and affective functioning and that is frequently under-diagnosed. To enhance clinical detection of catatonia, this study aimed to develop a rapid, sensitive Catatonia Quick Screen (CQS) using a reduced set of catatonic signs to facilitate screening in adult and pediatric patients.

Methods

Data were derived from two retrospective cohorts totaling 446 patients (254 adults, 192 children) who screened positive for catatonia using the Bush Francis Catatonia Screening Instrument (BFCSI). Sensitivity analyses were performed for all combinations of BFCSI signs, with sensitivity defined as the proportion of patients identified by each subset relative to the full BFCSI. The CQS was developed by selecting signs from the BFCSI based on sensitivity, ease of assessment, and relevance to diverse catatonia presentations.

Results

Screening for the presence of any one of four signs—excitement, mutism, staring, or posturing—using the CQS yielded a theoretical sensitivity of 97% (95% CI: 95 to 98%) relative to the full BFCSI (which requires two signs out of 14). The CQS demonstrated 97% sensitivity across both pediatric and adult subsets.

Conclusion

The Catatonia Quick Screen provides a rapid screening alternative to the BFCSI with high sensitivity, potentially improving early detection of catatonia in clinical settings. Future prospective studies are necessary to validate the CQS’s sensitivity and to determine its specificity in clinical populations.

Significant Outcomes

The Catatonia Quick Scale (CQS) is a newly developed rapid screen for catatonia.

Assessment for any one of four signs—excitement, mutism, staring, and posturing—has 97% sensitivity for detecting catatonia relative to the BFCSI.

This screening is sensitive in both adult and pediatric populations.

Limitations

The study relies on retrospective data.

Only patients who initially screened positive for catatonia were included, so the specificity of the CQS could not be assessed.

Most of the sample has a primary psychiatric diagnosis so the generalizability to patients with primary medical disorders is unclear.
Investigating causal relationships between loneliness, social isolation and health
Authors: Hilliard Darren D. , Wootton Robyn E. , Sallis Hannah M. , Van De Weijer Margot P. , Treur Jorien L. , Qualter Pamela , Dixon Padraig , Sanderson Eleanor C.M. , Carslake David J. , Richmond Rebecca C. , Beloe Patricia , Turner-Harris Lucy , Byatt Lauren Bowes , Munafò Marcus R. , Reed Zoe E.
Published: November 2024

Loneliness and social isolation are important public health concerns due to their associations with a range of health outcomes. However, it is difficult to ascertain whether loneliness and social isolation cause those outcomes or whether the observed associations are biased by confounding and reverse causation. In this study we used a triangulation approach combining observational analysis, sibling control design, and Mendelian Randomisation (a genetically informed causal inference approach), to draw robust conclusions about these relationships. Using a combination of publicly available genome-wide association study (N= 17,526 to 2,083,151) and UK Biobank data (N= 8,075 to 414,432), we examined relationships between loneliness and social isolation and outcomes related to physical health, mental health and wellbeing and general health (reflecting both physical and mental health e.g., multimorbidity). Our results provide evidence for causal effects of loneliness and social isolation on poorer mental health and wellbeing and of loneliness on poorer general health. Evidence was generally stronger for loneliness compared to social isolation. We do not find evidence of effects on specific physical health outcomes; however, we cannot definitively rule out causal relationships. Interventions targeting loneliness and social isolation may be effective strategies for improving general health, mental health and wellbeing outcomes.
Identification of a Highly Functional Effector CD8+T Cell Program after Transplantation in Mice and Humans
Authors: Cohen Gregory S. , Freibaum Joel S. , Leathem Riley P. , Hatano Ryo , Morimoto Chikao , Krummey Scott M.
Published: December 2024

Acute T cell mediated rejection of allografts remains a significant risk factor for early graft loss. Our prior work defined a population of graft-specific CD8+T cells positive for the activated receptor CD43 (expressing the 1B11 epitope) that form during acute rejection, leading us to further understand the in vivo fate and clinical relevance of this population. We found that during acute rejection, the CD43+ICOS+phenotype was sensitive for proliferative graft-specific CD8+T cells. We evaluated whether CD43 1B11 signaling could impact graft survival, and found that CD43 1B11 mAb treatment could overcome costimulation-blockade induced tolerance in the majority of mice. Using an adoptive transfer approach, we investigated the fate of CD43 1B11+and CD43 1B11-CD8+T cell populations, and found that CD43 1B11+CD8+T cells were more persistent three weeks after transplantation. A portion of CD43 1B11-CD8+T cells converted to CD43 1B11+, while CD43 1B11+CD8+T cells retained CD43 1B11+status. In healthy human donors, we found that the CD43 1D4 clone, which identifies the large CD43 isoform, defines a population of antigen-experienced CD8+T cells independent of the canonical CD8+T cell populations. CD43 1D4+CD8+T cells were efficient cytokine-producers after stimulation. In scRNA-seq analysis of graft-infiltrating cells from renal transplant patients experiencing acute rejection, a population of SPN+GCNT1+CD8+T cells had an effector phenotype that includes high expression of IFNG, ICOS, and perforins/granzymes. Together, these data provide evidence that the CD43 1B11 expression defines a proliferative and persistent population of CD8+T cells in mice, and that an analogous population of antigen-experienced CD8+T cells that participate in allograft rejection.
Optimization of a Multi-Feature AI Ensemble and Voting System for MAPKAPK2 Inhibitor Discovery
Authors: Chen Hayden
Published: December 2024

1.

The identification of an effective inhibitor is an essential starting point in drug discovery. Unfortunately, many issues arise with conventional high-throughput screening methods. Thus, new strategies are needed to filter through large compound screening libraries to create target-focused, smaller libraries. Effective computational methods in this respect have emerged in the past decade or so; among these methods is machine learning. Herein, we explore an ensemble Deep Learning model trained on MAPKAPK2 bioactivity data. This ensemble ML model consists of ten individual models trained on different features, each optimized for MAPKAPK2 inhibitor identification. Voting systems were established alongside the model. Using these voting systems, the ensemble model achieved an accuracy score of 0.969 and precision score of 0.964 on a testing set, in addition to reporting a false positive rate of 0.014 on an inactive compound set. The reported metrics indicate an effective initial step for novel MAPKAPK2 inhibitor identification and subsequent drug development, with applicability to other kinase targets.
Bayesian phylodynamic inference of multi-type population trajectories using genomic data
Authors: Vaughan Timothy G. , Stadler Tanja
Published: December 2024

Phylodynamic methods provide a coherent framework for the inference of population parameters directly from genetic data. They are an important tool for understanding both the spread of epidemics as well as long-term macroevolutionary trends in speciation and extinction. In particular, phylodynamic methods based on multi-type birth-death models have been used to infer the evolution of discrete traits, the movement of individuals or pathogens between geographic locations or host types, and the transition of infected individuals between disease stages. In these models, population heterogeneity is treated by assigning individuals to different discrete types. Typically, methods which allow inference of parameters under multi-type birth-death models integrate over the possible birth-death trajectories (i.e. the type-specific population size functions) to reduce the computational demands of the inference. As a result, it has not been possible to use these methods to directly infer the dynamics of trait-specific population sizes, infected host counts or other such demographic quantities. In this paper we present a method which infers these multi-type trajectories with almost no additional computational cost beyond that of existing methods. We demonstrate the practicality of our approach by applying it to a previously-published set of MERS-CoV genomes, inferring the numbers of human and camel cases through time, together with the number and timing of spillovers from the camel reservoir. This application highlights the multi-type population trajectory’s ability to elucidate properties of the population which are not directly ancestral to its sampled members.
The high quality Chinese white truffle genome and novel fossil-calibrated estimate of Pezizomycetes divergence reveal the tempo and mode of true truffles genome evolution
Authors: Martelossi Jacopo , Vujovic Jacopo , Huang Yue , Tatti Alessia , Xu Kaiwei , Puliga Federico , Chen Yuanxue , Stabelli Omar Rota , Ghiselli Fabrizio , Zhang Xiaoping , Zambonelli Alessandra
Published: December 2024

The genusTuber(family: Tuberaceae) includes the most economically valuable ectomycorrhizal (ECM), truffle-forming fungi. Previous genomic analyses revealed that massive transposable element (TE) proliferation represents a convergent genomic feature of mycorrhizal fungi, including Tuberaceae. Repetitive sequences are one of the major drivers of genome evolution shaping its architecture and regulatory networks. In this context, Tuberaceae represent an important model system to study their genomic impact; however, the family lacks high-quality assemblies. Here, we tested the interplay between TEs and Tuberaceae genome evolution by producing a highly contiguous assembly for the endangered Chinese truffleTuber panzhihuanense, along with a novel timeline for Tuberaceae diversification and comprehensive comparative genomic analyses. We found that concurrently with a Paleogene diversification of the family, pre-existing Chromoviridae-related Gypsy clades independently expand in different truffle lineages leading to increased genome size and high gene family turnover rates, but without resulting in highly scrambled genomes. Additionally, we found an enrichment of ECM-induced gene families among ancestral duplication events. Finally, we explored the repetitive structure of nuclear ribosomal DNA (rDNA) loci for the first time in the clade. We found that most of the 45S rDNA paralogues are undergoing concerted evolution, though an isolated divergent locus raises concerns about potential issues for metabarcoding and biodiversity assessments. Our study provides a fundamental genomic resource for future research on truffle genomics and showcases a clear example on how establishment and self-perpetuating expansion of heterochromatin can drive massive genome size variation due to activity of selfish genetic elements.
Comprehensive Enumeration of Cancer Stem-like Cell Heterogeneity Using Deep Neural Network
Authors: Chowdhury Debojyoti , Priyadarshi Shreyansh , Biswas Sayan , Neekhra Bhavesh , Gupta Debayan , Haldar Shubhasis
Published: December 2024

Cancer stem cells (CSCs), a distinct subpopulation within tumors, are pivotal in driving treatment resistance and tumor recurrence, posing substantial challenges to conventional therapeutic strategies. Precise quantification and profiling of these cells are essential for improving cancer treatment outcomes. We present ACSCeND, an advanced deep neural network model accompanied by a robust workflow, specifically developed to quantify cellular compositions from bulk RNA-seq data, enabling accurate CSC profiling. By integrating bulk RNA-seq data with insights derived from single-cell RNA-seq datasets, ACSCeND effectively captures the diversity and hierarchical organization of tumor-resident cell states, alongside cell-specific gene expression profiles (GEPs). Compared to current tissue deconvolution models, ACSCeND exhibits superior performance, achieving significantly higher Concordance Correlation Coefficient (CCC) values and lower Root Mean Square Error (RMSE) across various pseudobulk and real-world bulk tissue samples. Application of ACSCeND to TCGA and PRECOG datasets reveals a strong association between CSC abundance and poorer disease-free survival outcomes, underscoring the clinical relevance of CSCs in cancer progression. Furthermore, cell-specific GEPs for distinct CSC states unveil novel molecular signatures and illuminate the origins of CSC-driven tumor heterogeneity. In summary, ACSCeND provides a powerful, scalable platform for high-throughput quantification of cellular compositions and distinct potency states within normal tissues as well as highly heterogeneous tissues, such as tumors.
Identifying Family Structures from Obituaries and Matching them to Patients in an Electronic Heath Record
Authors: Mayer John , Delgoffe Brooke , Hebbring Scott
Published: December 2024

Motivation

Family data is a valuable data source in bioinformatic research. This is because family members often share common genetic and environmental exposures. Collecting this family data is traditionally very labor intensive but advances in electronic health record (EHR) data mining has proven useful when identifying pedigrees linked to longitudinal health histories. These are called e-pedigrees. Unfortunately, e-pedigrees tend to miss the oldest generations who inherently have the longest and richest health histories. A good source of family data from older generations includes obituaries, as they have a formulaic nature making them a good candidate for natural language processing that can extract relationships to the decedent. While there have been several studies on obtaining such data from obituaries, we demonstrate for the first-time approaches that tie that information to an EHR.

Results

NLP extraction resulted in 8,166,534 family members being abstracted from 567,279 obituaries published in the state of Wisconsin. After matching decedent and family members to patients in the EHR, we identified 109,365 unique patients that were put in 34,158 pedigrees. The largest pedigree consisted of 21 individuals. Heritability of adult height was quantified (H2= 0.51 +- .04, P=< 1.00e-07) demonstrating this data’s use in genetic research. The heritability data, coupled with overlapping data in a biobank, suggested 80% - 90% of familial relationships were accurately defined. The totality of these findings demonstrate obituaries with the oldest generations can be highly informative for bioinformatic research.

Availability and Implementation

Code is available on GitHub athttps://github.com/jgmayer672/ObituaryNLP.
Approximate Bayesian computation supports a high incidence of chromosomal mosaicism in blastocyst-stage human embryos
Authors: Yang Qingya , Carioscia Sara A. , Isada Matthew , McCoy Rajiv C.
Published: December 2024

Chromosome mis-segregation is common in human meiosis and mitosis, and the resulting aneuploidies are the leading cause of pregnancy loss. Preimplantation genetic testing for aneuploidy (PGT-A) seeks to prioritize chromosomally normal embryos for transfer based on genetic analysis of a biopsy of approximately five trophectoderm cells from blastocyst-stagein vitrofertilized (IVF) embryos. While modern PGT-A platforms classify these biopsies as aneuploid, euploid, or mosaic (possessing a mixture of normal and aneuploid cells), the underlying incidences of aneuploid, euploid, and mosaic embryos and the rates of meiotic and mitotic error that produced them remain largely unknown. To address this knowledge gap, we paired a recent method for embryo simulation with approximate Bayesian computation (ABC) to infer rates of meiotic and mitotic error that best explain published PGT-A data. By simulating from these posterior distributions, we also evaluated the chromosomal status of entire embryos. For a published clinical sample, we estimated a 39-43% probability of meiotic error per meiosis, as well as a 1.0-3.0% probability of mitotic error per mitosis, depending on assumptions about spatial clustering of aneuploid cells within mosaic embryos. In addition, our analyses suggest that less than 1% of blastocysts are fully euploid, and that many embryos possess low-level mosaic clones that are not captured during biopsy. These broad conclusions were relatively insensitive to potential misclassification of mosaic biopsies. Together, our work helps overcome the limitations of embryo biopsies to estimate the fundamental rates of cell division errors that are the main causes of human pregnancy loss.
Adherent-to-suspension transition promotes melanoma metastatic dissemination
Authors: Lee Dong Ki , Oh Jongwook , Lee Soyeon , Huh Hyunbin D. , Sub Yujin , Park Hyun Woo , Gee Heon Yung
Published: December 2024

Melanoma is a highly metastatic skin cancer that often evades current therapeutic strategies primarily because of the complex mechanisms involved in metastasis. This study investigated the role of adherent-to-suspension transition (AST) in melanoma and its potential to facilitate metastasis by reprogramming cellular anchorage dependency. Using melanoma models, we demonstrated that the AST factors IKZF1, IRF8, and NFE2 are crucial for reprogramming, influencing gene expression related to cell adhesion and survival. Notably, our results highlight that AST factor expression undergoes dynamic changes during metastasis, which can be reversed in circulating tumor cells. Our findings revealed that AST contributes to the increased metastatic potential and invasiveness of melanoma cells and underscores its role independent of the epithelial-to-mesenchymal-like transition pathways. Based on the results, we highlight the potential of targeting AST mechanisms to develop new therapeutic strategies against metastasis.
Remodelling of plasma lipoproteins by icosapent ethyl -supplementation and its impact on cardiovascular disease risk markers in normolipidemic individuals
Authors: Äikäs Lauri , Kovanen Petri T. , Lorey Martina , Laaksonen Reijo , Holopainen Minna , Ruhanen Hanna , Käkelä Reijo , Jauhiainen Matti , Hermansson Martin , Öörni Katariina
Published: November 2024

BACKGROUND AND AIMS

Icosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), can reduce cardiovascular disease (CVD). We examined the effect of IPE-supplementation on lipoprotein subclasses, lipidomes and atherogenic properties.

METHODS

Normolipidemic volunteers received daily 3.9g of IPE for 28 days. Using three independent metabolomic platforms, the fatty acid and lipoprotein profiles in plasma, and lipidomes of isolated VLDL, LDL and HDL, were determined. Aggregation propensity of LDL and the proteoglycan-binding of apoB-containing plasma lipoproteins, and the cholesterol efflux– inducing capacity of HDL were determined.

RESULTS

IPE-supplementation increased plasma EPA concentrations by 4-fold with consequent reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids. This resulted in reduction of multiple clinical risk markers, including triglyceride-, remnant cholesterol-, and apoB-levels, and 10-year CVD risk score. IPE induced uniform alterations across all lipoprotein classes. However, intrinsic interindividual differences in lipoprotein lipidomes outweighed IPE-induced changes. IPE did not alter LDL aggregation propensity or HDL-mediated cholesterol efflux but reduced the affinity of apoB-lipoproteins for proteoglycans. This correlated with decreased apoB-particle concentration and cholesterol content, alongside changes in specific lipid species in LDL, notably phosphatidylcholine 38:3 previously associated with CVD.

CONCLUSIONS

IPE-supplementation rapidly increases circulating EPA, which integrates equally into all lipoprotein classes. Reduced proteoglycan binding of apoB-lipoproteins likely contributes to the known IPE-induced reduction in CVD risk. Features associated with increased lipoprotein proteoglycan-binding included characteristics of metabolic syndrome, and specific lipid species. The data underscore persistence of distinct interindividual lipoprotein signatures despite extensive IPE-induced remodelling, highlighting the need for personalised approaches in ASCVD-treatment.

STRUCTURED GRAPHICAL ABSTRACT

Graphical Abstract:

The figure summarizes the study design and the main findings of this study. CVD, cardiovascular disease; EPA, eicosapentaenoic acid; FA fatty acid; IPE, icosapent ethyl; LDL, low-density lipoprotein; NMR, nuclear magnetic resonance (spectroscopy). Figure created withBioRender.com.