bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction and external validation of a scoring prediction model for mortality risk within 30 days of community-acquired pneumonia in children admitted to the pediatric intensive care unit: A multicenter retrospective case-control study
Authors: Cheng Xingfeng , Wang Huizhen , Sun Lingli , Ge Wei , Liu Rui , Qin Hua , Zhang Yong , Li Changjian
Published: March 2024

In this study, we constructed and validated a scoring prediction model to identify children admitted to the pediatric intensive care unit (PICU) with community-acquired pneumonia (CAP) at risk for early death. Children with CAP who were admitted to the PICU were included in the training set and divided into death and survival groups according to whether they died within 30 days of admission. For univariate and multifactorial analyses, demographic characteristics, vital signs at admission, and laboratory test results were collected separately from the 2 groups, and independent risk factors were derived to construct a scoring prediction model. The ability of the scoring model to predict CAP-related death was validated by including children with CAP hospitalized at 3 other centers during the same period in the external validation set. Overall, the training and validation sets included 296 and 170 children, respectively. Univariate and multifactorial analyses revealed that procalcitonin (PCT), lactate dehydrogenase (LDH), activated partial thromboplastin time (APTT), and fibrinogen (Fib) were independent risk factors. The constructed scoring prediction model scored 2 points each for PCT ≥ 0.375 ng/mL, LDH ≥ 490 U/L, and APTT ≥ 31.8 s and 1 point for Fib ≤ 1.78 g/L, with a total model score of 0–7 points. When the score was ≥ 5 points, the sensitivity and specificity of mortality diagnosis in children with CAP were 72.7% and 87.5%, respectively. In the external validation set, the sensitivity, specificity, and accuracy of the scoring model for predicting the risk of CAP-related death were 64.0%, 92.4%, and 88.2%, respectively. Constructing a scoring prediction model is worth promoting and can aid pediatricians in simply and rapidly evaluating the risk of death in children with CAP, particularly those with complex conditions.
Comparison of survival outcome of open, total laparoscopic, and laparoscopy-assisted radical vaginal hysterectomy for stage IB2 cervical cancer patients: A multicenter retrospective study
Authors: Yoon Hyung Joon , Kwon Byung Su , Rho Hyun Jin , Lee Tae Hwa , Jeong Dae Hoon , Kim Ki Hyung , Suh Dong Soo , Song Yong Jung
Published: March 2024

The aim of this study was to compare survival outcomes of 3 different radical hysterectomy (RH) types, namely total abdominal radical hysterectomy (TARH), total laparoscopic radical hysterectomy (TLRH), and laparoscopy-assisted radical vaginal hysterectomy (LARVH), in patients with FIGO stage IB2 cervical cancer. We retrospectively identified a cohort of patients who underwent RH for cervical cancer between 2010 and 2017. Patients with stage IB2 cervical cancer were included and were classified into TARH, TLRH, and LARVH treatment groups. Survival outcomes were estimated by the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazards models were fit to estimate the independent association of RH technique with outcome. 194 patients were included in this study: 79 patients in the TARH group, 55 in the TLRH group, and 60 in the LARVH group. No significant differences were found in clinicopathological characteristics between the 3 RH groups. On comparing survival outcomes with TARH, both TLRH and LARVH showed no significant difference in terms of 5-year overall survival (TARH vs TLRH, P = .121 and TARH vs LARVH, P = .436). Conversely, compared to the TARH group, 5-year progression-free survival (PFS) was significantly worse in the TLRH group (P = .034) but not in the LARVH group (P = .288). Multivariate analysis showed that TLRH surgical approach (hazard ratio, 3.232; 95% confidence interval, 1.238–8.438; P = .017) was an independent prognostic factor for PFS in patients with IB2 cervical cancer. Our study suggests that in patients with FIGO stage IB2 cervical cancer, among the minimally invasive RH approaches, TLRH and LARVH, only TLRH approach was associated with worse PFS when compared with the TARH approach.
Association between the quantitative characteristics of dual-energy spectral CT and cytoreduction surgery outcome in patients with advanced epithelial ovarian cancers: A prospective observational study
Authors: Xu Xiaojuan , Chen Yan , Zhang Xinxin , Wang Yilin
Published: March 2024

This study aimed to explore the association between the quantitative characteristics of dual-energy spectral CT and cytoreduction surgery outcome in patients with advanced epithelial ovarian carcinoma (EOC). In this prospective observational study, patients with advanced EOC (federation of gynecology and obstetrics stage III–IV) treated in the Department of Gynecological Oncology at our Hospital between June 2021 and March 2022 were enrolled. All participants underwent dual-energy spectral computed tomography (DECT) scanning 2 weeks before cytoreductive surgery. The quantitative data included peritoneal cancer index (PCI) determined by DECT, CT value at 70 keV, normalized iodine concentration, normalized water concentration, effective atomic number (effective-Z), and slopes of the spectral attenuation curves (slope λ Hounsfield unit). Fifty-five participants were included. The patients were 57.2 ± 9.8 years of age, and 72.7% were menopausal. The maximal diameter of tumors was 8.6 (range, 2.9–19.7) cm, and 76.4% were high-grade serous carcinomas. Optimal cytoreduction was achieved in 43 patients (78.2%). Compared with the optimal cytoreductive group, the suboptimal cytoreductive group showed a higher PCI (median, 21 vs 6, P < .001), higher 70 keV CT value (69.5 ± 16.6 vs 57.1 ± 13.0, P = .008), and higher slope λ Hounsfield unit (1.89 ± 0.66 vs 1.39 ± 0.60, P = .015). The multivariable analysis showed that the PCI (OR = 1.74, 95%CI: 1.24–2.44, P = .001) and 70 keV CT value (OR = 1.07, 95%CI: 1.01–1.13, P = .023) were independently associated with a suboptimal cytoreductive surgery. The area under the receiver operating characteristics curve of PCI and 70 keV CT value was 0.903 (95%CI: 0.805–1.000, P = .000) and 0.740 (95%CI: 0.581–0.899, P = .012), respectively. High PCI and 70 keV CT value are independently associated with suboptimal cytoreductive surgery in patients with advanced EOC. The PCI determined by DECT might be a better predictor for suboptimal cytoreduction.
Case report: A novel R246L mutation in the LMX1B homeodomain causes isolated nephropathy in a large Chinese family
Authors: Li Xian , Fan Jiaojiao , Fu Rong , Peng Ming , He Jujie , Chen Qiufang , Wang Shujing , Chen Chong
Published: March 2024

Background:

Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations.

Case presentation:

The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family.

Conclusions:

This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.
Comparison of vonoprazan-based dual therapy with vonoprazan-based bismuth quadruple therapy for treatment-naive patients with Helicobacter pylori infection: A propensity score matching analysis
Authors: Liu Zhu , Chen Xin , Sun Dong-Jie , Zhao Wen-Wen , Kou Luan , Zheng Wen-Wen , Hao Jiao-Rong , Gao Feng-Yu
Published: March 2024

Vonoprazan, a novel acid suppressant and the first potassium-competitive acid blocker, has the potential to enhance the eradication rate of Helicobacter pylori due to its robust acid-suppressing capacity. This study aimed to compare the efficacy of vonoprazan-based dual therapy (vonoprazan–amoxicillin, VA) with vonoprazan-based bismuth quadruple therapy (VBQT) as a first-line treatment for H pylori infection. This retrospective single-center non-inferiority study was conducted in China. Treatment-naive H pylori-positive patients aged 18 to 80 received one of the 2 treatment regimens at our center. The VA group received vonoprazan 20 mg twice daily and amoxicillin 1000 mg 3 times daily for 14 days, whereas the VBQT group received vonoprazan 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg twice daily for 14 days. The eradication rate was evaluated 4 to 6 weeks after treatment using the carbon-13/14 urea breath test. Propensity score matching was used to analyze eradication rates, adverse events (AEs), and patient compliance between the 2 groups. Initially, 501 patients were included, and after propensity score analysis, 156 patients were selected for the study. Intention-to-treat analysis showed eradication rates of 87.2% (95% CI, 79.8–94.6%) for the VA group and 79.5% (95% CI, 70.5–88.4%) for the VBQT group (P = .195). Per-protocol analysis demonstrated rates of 94.4% (95% CI, 89.2–99.7%) for the VA group and 96.8% (95% CI, 92.4–100%) for the VBQT group (P = .507). Non-inferiority was confirmed between the 2 groups, with P values < .025. The VA group showed a lower rate of AEs (10.3% vs 17.9%, P = .250) compared to the VBQT group. There were no significant differences in patient compliance between the 2 groups. In treatment-naive patients with H pylori infection, both the 14-day VA and VBQT regimens demonstrated comparable efficacy, with excellent eradication rates. Moreover, due to reduced antibiotic usage, lower rate of AEs, and lower costs, VA dual therapy should be prioritized.
Mast Cell Sarcoma Mimicking Lymphoma or Metastatic Disease on 18F-FDG PET/CT
Authors: Rosar Florian , Ezziddin Samer , Bittenbring Jörg Thomas , Christofyllakis Konstantinos , Burgard Caroline
Published: March 2024

We report an18F-FDG PET/CT scan of a 47-year-old man diagnosed with diffuse mast cell sarcoma with lymph node, bone, liver, spleen, and lung involvement. This interesting image should remind colleagues to consider mast cell sarcoma as a rare differential diagnosis in patients with multiple, intensely hypermetabolic lesions in various organs and lymph nodes.
Dynamic Morphological Growth Trajectory of Crouzon Population: A Geometric Morphometric Analysis
Authors: Zhong Yehong , Chen Zhewei , Li Binghang , Ma Hengyuan , Yang Bin
Published: March 2024

This study is to visualize the morphological growth trajectory of the Crouzon population and provide a more comprehensive and perceptual understanding of pathologic aggregation in terms of maxillofacial and soft tissue surfaces. Twenty-two patients with Crouzon syndrome were included in this retrospective surgery. Preoperative computed tomography was segmented into maxillofacial and soft tissue surface morphologies. Fifty-two anatomical landmarks and a standardized template were used to extract the morphological phenotypes and transform them into spatial coordinates. Geometric morphometrics (GM) were applied to visualize the growth trajectory and estimate the morphological variation of the Crouzon population. Cephalometric analysis was conducted to validate the growth trajectory in a clinical aspect. It was found that both maxillofacial and soft tissue surface morphologies were strongly covaried with age. Morphological development of the Crouzon population was characterized by (1) maxillary retrusion and clockwise rotation, (2) mandibular counterclockwise rotation, (3) facial width narrowing and aggregated concave face, and (4) sunken nasal bone. Pathologic maxillary retrusion continuously existed from infancy to adulthood, and rapid aggravation took place at 3 to 6 years old. In conclusion, this study is the first to visualize the dynamic growth trajectories on both maxillofacial and soft tissue surface morphologies. More attention and monitoring of breathing, snoring, intelligence, and global development should be cast on Crouzon patients between 3 and 6 years old in family care. If any functional abnormalities occur during this period, professional consultations and evaluations should be conducted timely to avoid pathologic aggravation. Consistency between GMs and cephalometry validates the reliability of GM potentials in the clinical field, allowing a promising and revolutionary methodology for dynamically and qualitatively analyzing pathologic changes in some rare congenital diseases.
Postoperative Radiologic Imaging in Secondary Alveolar Bone Grafting for Cleft Lip and Palate: A Systematic Review and Meta-Analysis
Authors: Groff Connor K. , Obinero Chioma G. , Cepeda Alfredo , Barrera Jose E. , Sobol Danielle L. , Nguyen Phuong D. , Greives Matthew R.
Published: March 2024

Introduction:

Radiographs (XRs), computed tomography (CT) scans, and cone-beam CT (CBCT) scans are utilized for assessment of secondary alveolar bone graft (SABG) in patients with cleft lip and palate (CLP). However, the optimal choice for imaging modality remains unclear. This study compares the image fidelity and safety profile for XR, CT, and CBCT in the assessment of patients with CLP who have undergone SABG.

Methods:

Articles from MEDLINE and Elsevier Embase were screened. The primary outcome was graft success rate. Secondary outcomes were percent-by-volume of graft maintained and patient safety, defined by radiation exposure. A random effects model was used to calculate the pooled outcomes for each imaging modality. Chi-squared analysis was used to compare pooled outcomes between different imaging modalities.

Results:

Of the 149 articles identified initially, 14 were included. Computed tomography exhibited a significantly higher image fidelity demonstrated by a lower graft success rate (62.0%) compared with both XR (72.6%, P<0.01) and CBCT (69.8%, P<0.01). Cone-beam CT had the lowest reported percent-by-volume of graft maintained (32.1%). Computed tomography had a higher mean radiation dosage (39.7 milligray) than what has been reported for both XR and CBCT.

Conclusion:

Computed tomography demonstrated lower graft success rates than both XR and CBCT, possibly indicating a higher image fidelity. However, compared with CBCT, CT may have a higher radiation exposure. Randomized trials and longitudinal studies are necessary to perform a direct comparison between CT and CBCT and to correlate the image fidelity of these modalities with clinical outcomes.
Sarcopenia as the Mobility Phenotype of Aging: Clinical Implications
Authors: Ji Sunghwan , Jung Hee-Won , Baek Ji Yeon , Jang Il-Young , Lee Eunju
Published: March 2024

Sarcopenia, which is characterized by an age-related decline in muscle mass and function, poses significant challenges to geriatric care. Its definition has evolved from muscle-specific criteria to include muscle mass, muscle function, and physical performance, recognizing sarcopenia as a physical frailty. Sarcopenia is associated with adverse outcomes, including mortality, falls, fractures, cognitive decline, and admission to long-term care facilities. Neuromechanical factors, protein-energy balance, and muscle protein synthesis-breakdown mechanisms contribute to its pathophysiology. The identification of sarcopenia involves screening tests and a comprehensive assessment of muscle mass, strength, and physical function. Clinical approaches aligned with the principles of comprehensive geriatric assessment prioritize patient-centered care. This assessment aids in identifying issues related to activities of daily living, cognition, mood, nutrition, and social support, alongside other aspects. The general approach to factors underlying muscle loss and functional decline in patients with sarcopenia includes managing chronic diseases and evaluating administered medications, with interventions including exercise and nutrition, as well as evolving pharmacological options. Ongoing research targeting pathways, such as myostatin-activin and exercise mimetics, holds promise for pharmacological interventions. In summary, sarcopenia requires a multifaceted approach, acknowledging its complex etiology and tailoring interventions to individual patient needs.
Targeted Coaching to Improve Osteoporosis Therapy Adherence: A Single Arm Variation of the C-STOP Study
Authors: Ye Carrie , McAlister Finlay A. , Bellerose Debbie , Lin Meng
Published: March 2024

Background: In this pre-planned variation of the Comparing Strategies Targeting Osteoporosis to Prevent Fractures After an Upper Extremity Fracture (C-STOP) trial, we investigated whether adherence-specific coaching by the case manager (CM) further improved the adherence and persistence rates compared to those seen in the C-STOP trial. Methods: We conducted a prospective observational cohort study of community-dwelling adults 50 years or older who suffered an upper-extremity fracture and were not previously treated with osteoporosis medications, to assess whether a well-trained CM can partner with patients to improve adherence to and persistence with oral bisphosphonate intake. The primary outcome was adherence (taking > 80% of prescribed doses) to oral bisphosphonate intake at 12 months after study enrollment. Secondary outcomes included primary adherence to and 12-month persistence with oral bisphosphonate and calcium and vitamin D supplement intake at 12 months. Results: The study cohort consisted of 84 participants, of which 30 were prescribed an oral bisphosphonate. Twenty-two (73.3%) started treatment within 3 months. The adherence rate at 12 months was 77.3%. The persistence rate at 12 months was 95.5%. Of those not prescribed an oral bisphosphonate, 62.8% were taking supplemental calcium and 93.0% were taking supplemental vitamin D at 12 months. Depression was a significant predictor of 12-month non-adherence (adjusted odds ratio, 9.8; 95% confidence interval, 1.2–81.5). Conclusions: Adherence-specific coaching by a CM did not further improve the level of medication adherence achieved in the original C-STOP study. Importantly, these results can inform adherence in future intervention studies.
Association between Fat Mass and Obesity-Related Transcript Polymorphisms and Osteoporosis Phenotypes
Authors: Dios Krisel De , Huynh Ngoc , Tran Thach S. , Center Jacqueline R. , Nguyen Tuan V.
Published: March 2024

Background: Common variants in the fat mass and obesity-related transcript (FTO) gene are related to body mass index and obesity, suggesting its potential association with bone mineral density (BMD) and fracture risk. This study sought to define the association between FTO gene variants and the following phenotypes: (1) BMD; (2) bone loss; and (3) fracture risk.Methods: This analysis was based on the Dubbo Osteoporosis Epidemiology Study that included 1,277 postmenopausal women aged ≥60 years living in Dubbo, Australia. BMD at the femoral neck and lumbar spine was measured biennially by dual energy X-ray absorptiometry (GE Lunar). Fractures were radiologically ascertained. Six single nucleotide polymorphisms (SNPs; rs1421085, rs1558902, rs1121980, rs17817449, rs9939609, and rs9930506) of the FTO gene were genotyped using TaqMan assay.Results: Women homozygous for the minor allele (GG) of rs9930506 had a significantly higher risk of hip fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.15–3.23) than those homozygous for the major allele (AA) after adjusting for potential confounding effects. Similar associations were also observed for the minor allele of rs1121980. However, there was no significant association between the FTO SNPs and BMD or the rate of bone loss.Conclusions: Common variations in the FTO gene are associated with a hip fracture risk in women, and the association is not mediated through BMD or bone loss.
The interactive effect of sustained sleep restriction and resistance exercise on skeletal muscle transcriptomics in young females
Authors: Knowles Olivia E. , Soria Megan , Saner Nicholas J. , Trewin Adam J. , Alexander Sarah E. , Roberts Spencer S.H. , Hiam Danielle , Garnham Andrew , Drinkwater Eric J. , Aisbett Brad , Lamon Séverine
Published: March 2024

Introduction

Both sleep loss and exercise regulate gene expression in skeletal muscle, yet little is known about how the interaction of these stressors affects the transcriptome. The aim of this study was to investigate the effect of nine nights of sleep restriction, with repeated resistance exercise (REx) sessions, on the skeletal muscle transcriptome of young, trained females.

Methods

Ten healthy females aged 18-35 years undertook a randomised cross-over study of nine nights’ sleep restriction (SR; 5-h time in bed) and normal sleep (NS; ≥7 h time in bed) with a minimum 6-week washout. Participants completed four REx sessions per condition (day 3, 5, 7 and 9). Muscle biopsies were collected both pre- and post-REx on days 3 and 9. Gene and protein expression were assessed by RNA sequencing and Western Blot, respectively.

Results

Three or nine nights of sleep restriction had no effect on the muscle transcriptome independently of exercise. However, close to 3000 transcripts were differentially regulated (FDR < 0.05) 48 h post the completion of three resistance exercise sessions in both NS and SR conditions. Only 39% of downregulated and 18% of upregulated genes were common between both conditions, indicating a moderating effect of sleep restriction on the response to exercise.

Conclusion

Sleep restriction and resistance exercise interacted to alter the enrichment of skeletal muscle transcriptomic pathways in young, resistance-trained females. Performing exercise when sleep restricted may not provide the same adaptive response for individuals as if they were fully rested.
Breathwork-Induced Psychedelic Experiences Modulate Neural Dynamics
Authors: Lewis-Healey Evan , Tagliazucchi Enzo , Canales-Johnson Andres , Bekinschtein Tristan
Published: March 2024

Breathwork is a term for an understudied school of practices that involve the intentional modulation of respiration to induce an altered state of consciousness (ASC). We map here the neural dynamics of mental content during breathwork, using a neurophenomenological approach by combining Temporal Experience Tracing, a quantitative phenomenological methodology that preserves the temporal dynamics of subjective experience, with low-density portable EEG devices for every session. Fourteen novice participants completed a series of up to 28 breathwork sessions - of 20, 40 or 60 minutes - in 28 days, yielding a neurophenomenological dataset of 301 breathwork sessions. Using hypothesis-driven and data-driven approaches, we found that positive psychedelic-like subjective experiences that occurred within the breathwork sessions were associated with increased neural Lempel-Ziv complexity. Further, exploratory analyses showed that the aperiodic exponent of the power spectral density (PSD) - but not oscillatory alpha power - was also associated with these psychedelic-like phenomenological substates. We demonstrate the strength of this neurophenomenological framework, maximising the concurrent data acquisition of brain activity and phenomenological dynamics in multiple experiential dimensions. Non-linear aspects of brain dynamics, like complexity and the aperiodic exponent of the PSD, neurally map both a data-driven complex composite of positive experiences, and hypothesis-driven aspects of psychedelic-like experience states such as high bliss.
Probabilistic Inference on Virtual Brain Models of Disorders
Authors: Hashemi Meysam , Ziaeemehr Abolfazl , Woodman Marmaduke M. , Petkoski Spase , Jirsa Viktor K.
Published: March 2024

Connectome-based models, also known as Virtual Brain Models (VBMs), have been well established in network neuroscience to investigate pathophysiological causes underlying a large range of brain diseases. The integration of an individual’s brain imaging data in VBMs has improved patient-specific predictivity, although Bayesian estimation of spatially distributed parameters remains challenging even with state-of-the-art Monte Carlo sampling. VBMs imply latent nonlinear state space models driven by noise and network input, necessitating advanced probabilistic machine learning techniques for widely applicable Bayesian estimation. Here we present Simulation-Based Inference on Virtual Brain Models (SBI-VBMs), and demonstrate that training deep neural networks on both spatio-temporal and functional features allows for accurate estimation of generative parameters in brain disorders. The systematic use of brain stimulation provides an effective remedy for the non-identifiability issue in estimating the degradation of intra-hemispheric connections. By prioritizing model structure over data, we show that the hierarchical structure in SBI-VBMs renders the inference more effective, precise and biologically plausible. This approach could broadly advance precision medicine by enabling fast and reliable prediction of patient-specific brain disorders.
A chromosome-level genome assembly ofDrosophila madeirensis, a fruit fly species endemic to the island of Madeira
Authors: Tomihara Kenta , Llopart Ana , Yamamoto Daisuke
Published: March 2024

Drosophila subobscurais distributed across Europe, the Near East, and the Americas, while its sister species,D. madeirensis, is endemic to the island of Madeira in the Atlantic Ocean.D. subobscurais known for its strict light-dependence in mating and its unique courtship displays, including nuptial gift giving.D. subobscurahas also attracted the interest of researchers because of its abundant variations in chromosomal polymorphisms correlated to the latitude and season, which have been used as a tool to track global climate warming. AlthoughD. madeirensiscan be an important resource for understanding the evolutionary underpinning of these genetic characteristics ofD. subobscura, little work has been done on the biology of this species. Here, we used a HiFi long-read sequencing dataset to produce ade novogenome assembly forD. madeirensis. This assembly comprises a total of 111 contigs spanning 135.5 Mb, and has an N50 of 24.2 Mb and a BUSCO completeness score of 98.6%. Each of the six chromosomes ofD. madeirensisconsisted of a single contig. Breakpoints of the chromosomal inversions betweenD. subobscuraandD. madeirensiswere characterized using this genome assembly, updating some of the previously identified locations.
Emergence of a synergistic scaffold in the brains of human infants
Authors: Varley Thomas F. , Sporns Olaf , Stevenson Nathan J. , Welch Martha G. , Myers Michael M. , Vanhatalo Sampsa , Tokariev Anton
Published: March 2024

The human brain is a complex organ comprising billions of interconnected neurons which enables interaction with both physical and social environments. Neural dynamics of the whole brain go far beyond just the sum of its individual elements; a property known as “synergy”. Previously it has been shown that synergy is crucial for many complex brain functions and cognition, however, it remains unknown how and when the large number of discrete neurons evolve into the unified system able to support synergistic interactions. Here we analysed high-density electroencephalography data from late fetal to early postnatal period. We found that the human brain transitions from redundancy-dominated to synergy-dominated system around birth. Frontal regions lead the emergence of a synergistic scaffold comprised of overlapping subsystems, while the integration of sensory areas developed gradually, from occipital to central regions. Strikingly, early developmental trajectories of brain synergy were modulated by environmental enrichment associated with enhanced mother-infant interactions, and the level of synergy near term equivalent age was associated with later neurocognitive development.
In silicomodelling of CD8 T cell immune response links genetic regulation to population dynamics
Authors: Nguyen Thi Nhu Thao , Martin Madge , Arpin Christophe , Bernard Samuel , Gandrillon Olivier , Crauste Fabien
Published: March 2024

The CD8 T cell immune response operates at multiple temporal and spatial scales, including all the early complex biochemical and biomechanical processes, up to long term cell population behavior.

In order to model this response, we devised a multiscale agent-based approach using Simuscale software. Within each agent (cell) of our model, we introduced a gene regulatory network (GRN) based upon a piecewise deterministic Markov process (PDMP) formalism. Cell fate – differentiation, proliferation, death – was coupled to the state of the GRN through rule-based mechanisms. Cells interact in a 3D computational domain and signal to each other via cell-cell contacts, influencing the GRN behavior.

Results show the ability of the model to correctly capture both population behaviour and molecular time-dependent evolution. We examined the impact of several parameters on molecular and population dynamics, and demonstrated the add-on value of using a multiscale approach by showing that a higher degradation rate for the protein controlling cell death induces a later peak in the response.
Adaptation during the transition fromOphiocordycepsentomopathogen to insect associate is accompanied by gene loss and intensified selection
Authors: Ward Chris M. , Onetto Cristobal A. , Borneman Anthony R.
Published: March 2024

Fungal and bacterial symbiosis is an important adaptation that has occurred within many insect species, which usually results in the relaxation of selection across the symbiont genome. However, the evolutionary pressures and genomic consequences associated with this transition are not well understood. Pathogenic fungi of the genusOphiocordycepshave undergone multiple, independent transitions from pathogen to associate, infecting soft-scale insects trans-generationally without killing them. To gain an understanding of the genomic adaptations underlying this transition, long-read sequencing was utilized to assemble the genomes of bothParthenolecanium corniand itsOphiocordycepsassociate from a single insect. A highly contiguous haploid assembly was obtained forPart. corni, representing the first assembly from a single Coccoidea insect, in which 97% of its 227.8 Mb genome was contained within 24 contigs. Metagenomic-based binning produced a chromosome-level genome forPart. corni’sOphiocordycepsassociate. The associate genome contained 524 gene loss events compared to free-living pathogenicOphiocordycepsrelatives, with predicted roles in hyphal growth, cell wall integrity, metabolism, gene regulation and toxin production. Contrasting patterns of selection were observed between the nuclear and mitochondrial genomes specific to the associate lineage. Intensified selection was most frequently observed across nuclear orthologs, while selection on mitochondrial genes was found to be relaxed. Furthermore, scans for diversifying selection identified associate specific selection within three adjacent enzymes catalyzing acetoacetate’s metabolism to acetyl-COA. This work provides insight into the adaptive landscape during the transition to an associate life history, along with a base for future research into the genomic mechanisms underpinning the evolution ofOphiocordyceps.
Development of DuoMYC: a synthetic cell penetrant miniprotein that efficiently inhibits the oncogenic transcription factor MYC
Authors: Ellenbroek Brecht , Kahler Jan Pascal , Arella Damiano , Lin Cherina , Jespers Willem , Pomplun Sebastian
Published: March 2024

The master regulator transcription factor MYC is implicated in numerous human cancers, and its targeting is a long-standing challenge in drug development. MYC is a typical ‘undruggable’ target, with no binding pockets on its DNA binding domain and extensive intrinsically disordered regions. Rather than trying to target MYC directly with classical modalities, here we engineer synthetic cell penetrating miniproteins that can bind to MYC’s target DNA, the enhancer box (E-Box), with a high affinity and block MYC-driven transcription. We obtained the miniproteins via structure-based design and a combination of solid phase peptide synthesis and site-specific crosslinking. Our lead variant, DuoMYC, binds to E-Box DNA with high affinity (KD= 118 nM) and molecular dynamic simulations provide insights into the structural features leading to the high stability of that DNA binding complex. DuoMYC displays an excellent stability in human serum and is able to enter cells and inhibit MYC-driven transcription with submicromolar potency (IC50= 464 nM) as shown by reporter gene assay. Notably, DuoMYC surpasses the efficacy of several other recently developed MYC inhibitors. Our results highlight the potential of engineered synthetic protein therapeutics for addressing challenging intracellular targets.

Abstract Figure
Light and dopamine impact two circadian neurons to promote morning wakefulness
Authors: Le Jasmine Quynh , Ma Dingbang , Dai Xihuimin , Rosbash Michael
Published: March 2024

In both mammals and flies, circadian brain neurons orchestrate physiological oscillations and behaviors like wake and sleep; these neurons can be subdivided by morphology and by gene expression patterns. Recent single-cell sequencing studies identified 17Drosophilacircadian neuron groups. One of these include only two lateral neurons (LNs), which are marked by the expression of the neuropeptide ion transport peptide (ITP). Although these two ITP+LNs have long been grouped with five other circadian evening activity cells, inhibiting the two neurons alone strongly reduces morning activity; this indicates that they are prominent morning neurons. As dopamine signaling promotes activity inDrosophilalike in mammals, we considered that dopamine might influence this morning activity function. Moreover, the ITP+LNs express higher mRNA levels than other LNs of the type 1-like dopamine receptor Dop1R1. Consistent with the importance of Dop1R1, CRISPR/Cas9 mutagenesis of this receptor only in the two ITP+LNs renders flies significantly less active in the morning, andex vivolive imaging shows that dopamine increases cAMP levels in these two neurons; cell-specific mutagenesis ofDop1R1eliminates this cAMP response to dopamine. Notably, the response is more robust in the morning, reflecting higher morning Dop1R1 mRNA levels in the two neurons. As morning levels are not elevated in constant darkness, this suggests light-dependent upregulation of morning Dop1R1 transcript levels. Taken together with enhanced morning cAMP response to dopamine, the data indicate how light stimulates morning wakefulness in flies, which mimics the important effect of light on morning wakefulness in humans.
Identification of Potential Therapeutic Targets and Biomarkers for Glioblastomas Through Integrative Analysis of Gene Expression Data
Authors: Bautista Angélica , Romero Ricardo
Published: March 2024

Background

In this study, we conducted a comprehensive analysis of differential gene expression data from studies GSE15824, GSE4290 and GEPIA2 data to identify up-regulated hub genes with potential as therapeutic targets for glioblastomas. Through virtual screening, we also aimed to identify novel VEGFA inhibitors.

Results

Seven up-regulated hub genes (TYROBP, ITGB2, C1QA, C1QB, CTSS, TLR2, and CD163) were identified. Virtual screening of VEGFA inhibitors led to the discovery of six significant hits, including three from the ChemDiv library (D519-0372, G868-0191, and Y031-5201) and three from the ZINC20 database (ZINC57658, ZINC57652, ZINC57679). Molecular dynamics simulations highlighted G868-0191 as the most stable VEGFA inhibitor. Two repurposed drugs, Sunitinib and Ticlopidine hydrochloride, were also identified as potential candidates. In addition, the down-regulated hub genes GABARAPL1, OPTN, and CDH8 were proposed as potential biomarkers for glioblastomas.

Conclusion

This study underscores the significance of immune-related hub genes in glioblastoma pathology and suggests new VEGFA inhibitors as promising therapeutic agents. The identification of down-regulated genes as potential biomarkers offers further avenues for clinical application. However, experimental validation is needed to confirm the clinical utility of these findings.
EyeHex toolbox for complete segmentation of ommatidia in fruit fly eyes
Authors: Tran Huy , Dostatni Nathalie , Ramaekers Ariane
Published: March 2024

Variation inDrosophilacompound eye size is studied in various research contexts ranging from evolutionary to biomedical studies. Studying this variation requires the collection of large datasets required for the statistical power of the subsequent analyses. EyeHex is a new tool that automatically and fully segments fruit fly compound eyes from both brightfield and scanning electron microscopy images. The system comprises two modules. The first module uses machine-learning to extract the compound eye and ommatidia regions from different types of images. The second module is hard-coded and accurately determines the number and location of individual ommatidia using the hexagonal arrangement of the compound eye. EyeHex is equipped with a manual correction tool that enables control over segmentation accuracy, particularly at the edges of the eyes where ommatidia detection is more challenging due to highly slanted imaging angles and interfering ocular hairs. EyeHex is accompanied by an analysis tool to quantify ommatidia count, position, altitude, density across the eye, and arrangement along the anterior/posterior. Training and applying EyeHex model for ommatidia segmentation requires limited user inputs. It achieves a high level of accuracy (>99% when compared to manual counting) from both Scanning Electron Microscope and multi-focus brightfield images of twoDrosophila melanogasterstrains. This demonstrates that EyeHex can be integrated flexibly in a cheap and fast pipeline to extract statistics on variations ofDrosophilacompound eyes.
Inducible deletion ofEzh2in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/lprlupus-prone mice
Authors: Zheng Xiaoqing , Dozmorov Mikhail G , Espinoza Luis , Bowes Mckenna M , Bastacky Sheldon , Sawalha Amr H
Published: March 2024

Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4+ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4+ T cellEzh2conditional knockout mouse on the MRL/lprlupus-prone background. We demonstrate thatEzh2deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programed cell death pathways in EZH2-deficient mice.Ezh2deletion in CD4+ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4+ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.
[225Ac]Ac/[89Zr]Zr-labeled N4MU01 radioimmunoconjugates as theranostics against nectin-4 positive triple negative breast cancer
Authors: Babeker Hanan , Njotu Fabrice Ngoh , Ketchemen Jessica Pougoue , Tikum Anjong Florence , Doroudi Alireza , Nwangele Emmanuel , Uppalapati Maruti , Fonge Humphrey
Published: March 2024

Purpose

Nectin-4 is an overexpressed biomarker in 60-70% of triple-negative breast cancer (TNBC), and an ideal target for radiotherapy and PET imaging. In this study, we have developed theranostic radioimmunoconjugates (RICs) based on a fully-human anti-nectin-4 antibody, N4MU01. We characterized and evaluated the efficacy of these RICs for applications in molecular imaging and radiotherapy of aggressive TNBC models.

Methods

An anti-nectin-4 antibody (N4MU01) was radiolabeled with89Zr and225Ac, for imaging and radiotherapy, respectively, using TNBC xenograft and syngeneic models. Biodistribution & PET imaging of [89Zr]Zr-DFO-N4MU01 RIC was studied in mice bearing nectin-4 positive xenografts. Dosimetry of [225Ac]Ac-Macropa-N4MU01 was studied in healthy mice, and therapeutic efficacy was evaluated in mice bearing human TNBC MDA-MB-468 xenograft and in a syngeneic xenograft model using murine 4T1 breast cancer cells transfected with human nectin-4 (4T1.nectin-4). Mice received 2 doses of 13 kBq or 18.6 kBq 10 days apart.

Results

The pharmacokinetic profile of [89Zr]Zr-DFO-N4MU01 RIC showed biphasic distribution with a moderate elimination half-life of 63 h. PET imaging and biodistribution of [89Zr]Zr-DFO-N4MU01 in mice bearing MDA-MB-468 xenograft showed high tumor uptake of 13.2 ± 1.12 %IA/g at 120 h. [225Ac]Ac-Macropa-N4MU01 was effectively internalized in MDA-MB-468 and was cytotoxic to the cells with IC50of 1.2 kBq/mL. Mice bearing MDA-MB-468 xenograft treated with [225Ac]Ac-Macropa-N4MU01 (13 kBq or 18.6 kBq) had a remarkable tumor growth inhibition that was dose dependent. For the syngeneic 4T1.nectin-4model, treatment with [225Ac]Ac-Macropa-N4MU01 (13 kBq) led to complete tumor remission in 83.3% (5/6) of mice.

Conclusion

The specific tumor uptake and remarkable effectiveness at shrinking aggressive TNBC tumors is very promising towards clinical development of N4MU01 RICs as theranostics against TNBC.
Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine
Authors: Doyle Michelle R. , Beltran Nina M. , Bushnell Mark S. A. , Syed Maaz , Acosta Valeria , Desai Marisa , Rice Kenner C. , Serafine Katherine M. , Gould Georgianna G. , Daws Lynette C. , Collins Gregory T.
Published: March 2024

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long– or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ∼30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long– and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long– and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2or D3receptors, or 5-HT1B, 5-HT2A, or 5-HT2Creceptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.
Proteogenomic analysis reveals adaptive strategies to alleviate the consequences of aneuploidy in cancer
Authors: Boekenkamp Jan-Eric , Keuper Kristina , Redel Stefan , Barthel Karen , Johnson Leah , Wieland Angela , Räschle Markus , Storchova Zuzana
Published: March 2024

Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performedin vitroevolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors required for adaptation to aneuploidyin vitroand in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosome impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.