bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between subtypes of diabetes and special sensations: A 2-sample Mendelian randomization study
Authors: Liu Shihan , Lei Zhongli , Huang Guoxi , Zhang Lingli , Luo Wenlong , Yang Jinxiong
Published: January 2025

Diabetes, a chronic condition affecting millions of individuals, is divided into type 1 diabetes (T1D) and type 2 diabetes (T2D), each with unique pathophysiological characteristics. While the impact of diabetes on vision is established, its relationship with other special senses, balance, hearing, and olfaction, remains uncertain. This study utilized a 2-sample Mendelian randomization (MR) approach to investigate the associations between diabetes subtypes and specific sensory disorders. We performed MR analysis using various methods (inverse variance weighting [IVW], MR-Egger, simple mode, weighted mode, weighted median, MR-PRESSO) to assess the causal relationships between diabetes subtypes and sensory disorders (vestibular dysfunction, sensorineural hearing loss, conductive hearing loss, and olfactory dysfunction). Different diabetes genome-wide association studies datasets were utilized for validation. MR analysis revealed no significant correlations between T1D or T2D and the sensory disorders studied. Interestingly, an initial signal suggested that T1D might increase the risk of conductive hearing loss (IVW: odds ratio = 1.120, 95% CI: 1.035–1.211, P = .005), but this finding was not supported by validation studies. No evidence of horizontal pleiotropy or heterogeneity was found (P > .05). Our MR analysis and subsequent validation revealed no significant associations between diabetes subtypes and special senses. The initial suggestion of an increased risk of conductive hearing loss in T1D patients was not confirmed. Future research should further explore the intricate relationships among diabetes, sensory functions, and other factors, as well as the potential effects of diabetes management on sensory health.
Development of a novel risk signature revealing prognostic and tumor microenvironmental features in breast cancer
Authors: Shen Yong , Jiang Binbin , Luo Yingbo , Zhang Zhiwei
Published: January 2025

This study aimed to devise a breast cancer (BC) risk signature for based on pyrimidine metabolism-related genes (PMRGs) to evaluate its prognostic value and association with drug sensitivity. Transcriptomic and clinical data were retrieved from The Cancer Genome Atlas database and Gene Expression Omnibus repository. Pyrimidine metabolism-associated genes were identified from the Molecular Signatures Database collection. A risk signature was constructed through Cox regression and Lasso regression methods. Further, the relationship between the PMRG-derived risk feature and clinicopathological characteristics, gene expression patterns, somatic mutations, drug susceptibility, and tumor immune microenvironment was thoroughly investigated, culminating in the development of a nomogram. PMRGs displayed differential expression and diverse somatic mutations in BC. Univariate Cox analysis identified 36 genes significantly associated with BC prognosis, leading to the categorization of 2 BC molecular subtypes with discernible differences in prognosis. Using Lasso Cox regression, a risk signature composed of 16 PMRGs was established, wherein high-risk scores were indicative of poor prognosis. The PMRG-derived risk feature was also related to chemotherapy regimens and showed significant correlations with sensitivity to multiple drugs. Furthermore, distinct tumor immune microenvironment properties, gene expression profiles, and somatic mutation patterns were evident across varying risk scores. Ultimately, a nomogram was constructed incorporating the PMRGs-based risk signature alongside stage, and chemotherapy status, demonstrating excellent performance in prognosis prediction. We successfully developed a PMRG-based BC risk signature that effectively combines with clinicopathological attributes for accurate prognosis assessment in BC.
Role of the SOX family in cancer immune evasion: Emerging player and promising therapeutic opportunities
Authors: Li Jinke , Xu Yawen , Han Yunying , Yang Aifu , Qian Miaoshan , Wang Bo
Published: January 2025

Cancer immune evasion is one of the important mechanisms for cancer development, which is essential to developing novel immunotherapeutic strategies. The SOX (SRY-related HMG-box) family of transcription factors plays a crucial role in normal physiology as well as in a variety of human diseases especially cancer. It has been shown that SOX is involved in cancer immune evasion processes. This mini-review aimed to summarize how SOX family members induce cancer immune evasion by regulating antigen presentation, shaping the tumor immunosuppressive milieu, and controlling regulatory immune checkpoint inhibitors like programmed death ligand 1. Thorough exploration of SOX family will help uncover the mechanism of cancer immune evasion, and provide new ideas and targets for the development of immunotherapy strategies.
A study on the correlation between hyperuricemia and lifestyle and dietary habits
Authors: Zhang Wei-Zheng , Peng Qi , Cai Xiang-Sheng , Jiang Gu-Li , Huang Jie-Jing , Lu Lan-Lan , Feng Wen-Zhuo , Yan Pei-Yu , Gu Jie-Ruo
Published: January 2025

This study aimed to compare whether differences in lifestyle and dietary habits have an impact on hyperuricemia and to provide a reliable basis for the health management of citizens in our city. A total of 10,883 subjects who did not suffer from hyperuricemia, was anticipated in this study in 2018. After 2 years of follow-up, 7727 did not suffer from hyperuricemia and 3156 suffered from hyperuricemia. Dietary habits and lifestyle were collected by questionnaire. Multivariate logistic regression was used to identify the risk factors of hyperuricemia. For the analysis of the amount of change in uric acid (UA) before and after 2 years, t-tests and spearman correlation were used to explore the differences between the groups, and the trend effect of each variable on the amount of change in uric acid was analyzed by linear regression equations. The results showed that the prevalence of hyperuricemia varied by sex, high-fat food, smoked and fried food, milk and soy products, sugary drinks, sleep time, and the degree of smoking and drinking. Among them, infrequent consumption of milk and soy products, and short sleep time were risk factors for hyperuricemia, and men were more likely to have elevated uric acid levels after 2 years. It is recommended that people with hyperuricemia should actively limit their intake of fried foods, alcohol, and purine-rich foods, increase their intake of milk and soy foods, increase their sleep time, and seek to improve kidney and liver function.
The efficacy of auricular acupressure combined with emotional freedom techniques on the postoperative pain and anxiety state of patients with lower limb fractures: A randomized clinical controlled trial
Authors: Zhou Xianglong , Zhang Guoqin , Chen Dandan , Yao Huiping , Wang Qi
Published: January 2025

Background:

Lower limb fractures cause local pain, swelling, ecchymosis, and dysfunction. Clinically, incision and reduction surgery are often employed to treat lower limb fractures. However, postoperative pain can be intense, leading to adverse emotions that hinder subsequent recovery.

Methods:

A total of 99 postoperative patients with lower limb fractures were randomly divided into 3 groups: the control group (routine care, 33 patients), the auricular acupressure group (routine care plus auricular acupressure, 33 patients), and the combined group (routine care, auricular acupressure, and emotional freedom techniques [EFT], 33 patients). Pain levels were measured using the visual analog scale (VAS), and anxiety levels were measured using the self-rating anxiety scale (SAS) at various time points post-intervention. Patient satisfaction with nursing care was also evaluated at the end of the intervention.

Results:

The VAS scores in the combined group were significantly lower than those in the auricular acupressure and control groups at 4, 12, 24, and 48 hours post-intervention (P < .05). Additionally, the SAS scores in the combined group were significantly lower than those in the auricular acupressure and control groups at 72 hours post-intervention (P < .05). The combined group also reported significantly higher satisfaction with nursing care compared to the other 2 groups at the end of the intervention (P < .05).

Conclusion:

Auricular acupressure combined with EFT effectively reduces pain levels, alleviates anxiety, and increases patient satisfaction with nursing care in postoperative patients with lower limb fractures.
Peritoneal dialysis-associated peritonitis caused by Coxiella Burnetii: A case report
Authors: Zhong Yue , Cai Ze-Yu , Wang Jun-Rui , Qi Qi-Ge , Hao Jian
Published: January 2025

Rationale:

Peritoneal dialysis (PD)-associated peritonitis (PDAP) is the leading cause of PD failure and discontinuation of PD. Several zoonotic pathogens could lead to the development of PDAP. Coxiella burnetii (C. burnetii) was a zoonotic pathogen and the cause of Q fever. However, reports of PDAP caused by C. burnetii are rare. We herein report the first case of PDAP caused by C. burnetii in mainland China.

Patients concerns:

A 45-year-old woman was admitted to our hospital with chief complaint of yellow and cloudy PD effluent for 2 days. She had undergone PD for 5 years due to end-stage renal disease. She was engaged in cattle and sheep breeding. The culture of PD effluent was negative, even for specific species, such as Mycobacteria and fungi.

Diagnoses:

The culture from the PD effluent tested positive for C. burnetii by adopting metagenomic next-generation sequencing on day 37. We diagnosed her as PDAP caused by C. burnetii.

Interventions:

Empirical treatment with multiple broad-spectrum antibiotics (including vancomycin, etimicin, piperacillin) was initially adopted. After identifying C. burnetii as the culprint as the PDAP, the regimen was changed to doxycycline (100 mg twice daily) and moxifloxacin (400 mg once daily) orally, leading to clinical improvement.

Outcomes:

The white blood cell count of the PD effluent decreased to within the normal range and the culture of PD effluent was negative for C. burnetii at the visit of 4 months after discharge. Also, there was no sign for recurrence.

Lessons:

Vigilance should be heightened for PDAP cases with negative culture of PD fluid and poor response to standard broad-spectrum antibiotic treatment, along with a history of cattle and sheep breeding. In such conditions, PD effluent should be tested to detect possible peritonitis caused by C. burnetii, even in patients without symptoms of fever. Prompt pathogen identification and appropriate treatment are crucial for clinical improvement of such cases.
Concurrent ANCA-associated vasculitis and IgG4-related disease in a patient with fever of unknown origin and acute kidney injury: A case report
Authors: Lee Soo Jin , Shin Yujin , Cha Seung Ah , Kim Kyoung Min , Kang Kyung Pyo
Published: January 2025

Rationale:

It is often challenging to differentiate between IgG4-related disease (IgG4-RD) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) due to their similar clinical presentations. Recently, growing evidence has suggested a strong connection between AAV and IgG4-RD.

Patient concerns:

A 60-year-old woman was transferred to our hospital with fever and kidney dysfunction. Abdominal computed tomography revealed widespread infiltrative lesions in both kidneys.

Diagnoses:

Laboratory tests and subsequent renal biopsy confirmed both antineutrophil cytoplasmic antibody-associated vasculitis and IgG4-related disease.

Interventions:

We initiated plasmapheresis, oral cyclophosphamide, and high-dose glucocorticoids for treatment. Despite this, the patient’s condition worsened, requiring emergency hemodialysis.

Outcomes:

After 3 months of continued immunosuppressive treatment, renal function improved and hemodialysis was discontinued.

Lessons:

Our case showed an overlap of AAV and IgG4‐RD, which might support the hypothesis of an overlap syndrome of AAV and IgG4-RD. Clinicians should have a high index of suspicion when diagnosing fever of unknown origin, with the possibility of overlapping AAV and IgG4-RD.
Patient-Centered Physical Activity Intervention in Lung Cancer Patients
Authors: Heredia Ciuró Alejandro , Martín Núñez Javier , Navas Otero Alba , Calvache Mateo Andrés , Torres Sánchez Irene , Granados Santiago María , Valenza Marie Carmen
Published: January 2025

Background

Increasing physical activity levels is a significant unmet need in cancer survivors, and it can likely be enhanced through a better understanding of the interventions developed. Some studies on patient-centered physical activity interventions have shown promising results in increasing daily activity levels among lung cancer survivors. However, the programs present a high heterogeneity, and there is no consensus on the parameters and their effectiveness.

Objective

To examine the effectiveness of patient-centered physical activity interventions on clinical severity and functional capacity in lung cancer patients.

Methods

A systematic review was performed on randomized controlled trials. A literature search was conducted using MEDLINE, Web of Science, Science Direct, and Cochrane Library (last search November 2023). The Cochrane tool and the Grading of Recommendations Assessment, Development, and Evaluation system were used for quality assessment. Pooled data were meta-analyzed for physical activity levels, functional capacity, and cancer-related symptoms.

Results

Fourteen studies, encompassing 1123 lung cancer patients, were included. The treatment status of patients varied. The components of the physical activity programs showed heterogeneity. Results revealed significant differences favoring patient-centered physical activity interventions over the control group for physical activity levels (P < .05), functional capacity (P < .001), and cancer-related symptoms (P < .05).

Conclusion

The results indicate that patient-centered physical activity programs positively enhance physical activity levels, improve functional capacity, and reduce cancer-related symptoms in patients with lung cancer.

Implications for Practice

Patient-centered physical activity interventions show promise in improving the care and management of lung cancer patients. These interventions provide a basis for encouraging lung cancer patients to actively participate in their treatment.
Reduction of Streak Artifacts in the Superior Vena Cava for Better Visualization of Mediastinal Structures Through Virtual Monoenergetic Reconstructions Using a Photon-counting Detector Computed Tomography
Authors: Thater Greta , Frerichs Isabel , Büttner Sylvia , Schoenberg Stefan O. , Froelich Matthias , Ayx Isabelle
Published: January 2025

Purpose:

Computed tomography (CT) is crucial in oncologic imaging for precise diagnosis and staging. Beam-hardening artifacts from contrast media in the superior vena cava can degrade image quality and obscure adjacent structures, complicating lymph node assessment. This study examines the use of virtual monoenergetic reconstruction with photon-counting detector CT (photon-counting CT) to mitigate these artifacts.

Materials and Methods:

The retrospective study included 50 patients who underwent thoracoabdominal scans. Virtual monoenergetic reconstructions at nine keV levels (60 to 140 keV) were analyzed for Hounsfield Unit (HU) stability, image noise, and artifact index in various regions of interest (ROIs): mediastinal adipose tissue (ROI 1 to 3) and vascular stations (ROI 4 to 6) were compared with reference tissue (ROI 7 to 8). The diagnostic image quality of the keV levels was assessed using a 5-point Likert Scale.

Results:

Lower keV values (60 to 80) exhibited higher image noise and lower HU stability in mediastinal adipose tissue compared with higher energies, with optimal noise reduction observed at 130 keV (ROI 1 to 3). HU stability in vascular structures (ROI 4 to 6) significantly improved above 80 keV, with the best performance at 140 keV. Artifact levels decreased progressively from 60 to 140 keV. Visually, keV levels of 110 keV (96% Likert ≥4) and 120 keV (60% Likert 4) were rated most diagnostically valuable, consistent with technical findings.

Conclusion:

Virtual monoenergetic reconstructions with photon-counting CT effectively reduce beam-hardening artifacts near the superior vena cava, enhancing the visualization of lymph nodes and adjacent structures. This technology advances oncologic imaging by improving diagnostic accuracy in areas previously affected by artifact-related image degradation.
Flavobacterium arundinis sp. nov., Flavobacterium calami sp. nov., Flavobacterium helocola sp. nov. and Flavobacterium flavipallidum sp. nov., isolated from stagnant water in a clump of Phragmites japonica Steud
Authors: Park Sunho , Kim Inhyup , Woo Haejin , Lee Hyunji , Yook Subin , Seo Taegun
Published: January 2025

Four novel bacterial strains were isolated from stagnant water in a clump of Phragmites japonica Steud. The four Gram-negative, facultatively anaerobic, rod-shaped, non-motile and yellow-coloured strains were designated as DGU11T, DGU38T, DGU41T and DGU99T. The four novel strains exhibited 16S rRNA gene similarities with their closest type strains, ranging from 95.7 to 98.7%, average nucleotide identity values from 75.3 to 95.6% and digital DNA–DNA hybridization values between 17.9 and 59.6%. The cells of strain DGU11T were non-motile and grew at 10−30°C (optimum 25 °C), a pH range of 4.0–12.0 (optimum 9.0) and in the presence of 0–1.0% sodium chloride (NaCl) (optimum 0%). The cells of strain DGU38T were non-motile and grew at 10−35°C (optimum 30 °C), a pH range of 4.0–8.0 (optimum 7.0) and at 0 –2.0% NaCl (optimum 0%). The cells of strain DGU41T were non-motile and grew at 15−50°C (optimum 30 °C), a pH range of 6.0–9.0 (optimum 7.0) and in the presence of 0% NaCl (optimum 0%). The cells of strain DGU99T were non-motile and grew at 15−35°C (optimum 25 °C), a pH range of 6.0–12.0 (optimum 9.0) and in the presence of 0 –2.0% NaCl (optimum 0%). The major fatty acid composition of the four novel strains was iso-C15:0 and C16:1
 ω7c/C16:1
 ω6c, which is similar to other Flavobacterium species. The proposed names of the novel strains are Flavobacterium arundinis sp. nov. (type strain DGU11T=KACC 23722T=TBRC 19004T), Flavobacterium calami sp. nov. (type strain DGU38T=KACC 23723T=TBRC 19005T), Flavobacterium helocola sp. nov. (type strain DGU41T=KACC 23724T=TBRC 19006T) and Flavobacterium flavipallidum sp. nov. (type strain DGU99T=KACC 23725T=TBRC 19007T).
Progress in the investigation of the Firmicutes/Bacteroidetes ratio as a potential pathogenic factor in ulcerative colitis
Authors: Yin Yu , Yang Tiezheng , Tian Ziyue , Shi Chong , Yan Chengqiu , Li Hui , Du Yu , Li Guofeng
Published: January 2025

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that presents significant challenges in terms of treatment owing to a pronounced likelihood of recurrence and an elevated risk of cancer development, thereby imposing substantial risks on affected individuals. The gut microbiota of Firmicutes and Bacteroidetes (F/B) can affect diseases associated with IBD, which is also a risk factor for breast cancer. This review discusses the hazards associated with UC, highlights the existing disparities in UC-associated gut microbiome research, explores the concept of the F/B ratio and scrutinizes its correlation with UC. Moreover, the differences in the F/B ratios between healthy individuals and those with UC were thoroughly examined. These findings suggest that an elevated F/B ratio may promote the occurrence and progression of UC. Consequently, the F/B ratio may play a significant role in UC by influencing gut microbiota composition and inflammatory responses, suggesting that future research should focus on this ratio as a potential biomarker for disease progression and therapeutic targets in managing UC.
Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging
Authors: Trumpff Caroline , Huang Qiuhan , Michelson Jeremy , Liu Cynthia C. , Shire David , Habeck Christian G. , Stern Yaakov , Picard Martin
Published: January 2025

Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1)cell-free mitochondrial DNA(cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2)growth differentiation factor 15(GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
Enhanced Calcium Signaling in BLA Pyramidal Neurons Underlies a Sex and Circuit Specific Amygdala Dysfunction After Global Cerebral Ischemia
Authors: Vigil Jose J. , Tiemeier Erika , Chalmers Nicholas E. , Herson Paco S. , Quillinan Nidia
Published: January 2025

While advances in resuscitation science have improved cardiac arrest survival, we lack therapies to improve cognitive-affective outcomes in this patient population. Our lab has previously identified cognitive dysfunction in a mouse model of global cerebral ischemia (GCI) which has been attributed to hippocampal neurodegeneration and impaired hippocampal plasticity. However, no study has attempted to identify amygdala dysfunction after GCI, despite clinical evidence of emotional dysfunction, such as anxiety and Post-Traumatic Stress Disorder (PTSD). Therefore, it is important to identify the effect that GCI has on the amygdala, the emotional center of the brain. Our lab has a well-developed, translatable mouse model of GCI, the cardiac arrest/cardiopulmonary resuscitation model (CA/CPR), that has been instrumental in assessing amygdala function after GCI. We have utilized the amygdala-dependent delay-fear conditioning (DFC) paradigm to assess associative learning and memory and have performed field excitatory post-synaptic potential (fEPSP) recordings in two circuits within the amygdala, as measures of amygdala function. We have found a sex- and circuit-specific deficit in LTP of the cortical input to the basolateral amygdala (BLA), after GCI, that corresponds with a male specific associative learning and memory deficit. We found no evidence that these deficits of amygdala function can be attributed to GCI-induced neurodegeneration within the amygdala or altered locomotor function. We did, however, find that neuronal dendritic spine calcium signaling dynamics are enhanced in male survivors of GCI and are likely contributing to the observed LTP deficit and ultimately the deficit in associative learning and memory processes.

Significance Statement

While cognitive dysfunction has been well characterized in CA/CPR survivors, the development of emotional dysfunction that may arise in survivors is understudied. Poor follow up of CA/CPR survivors has left a gap in our knowledge about the effect that GCI has on the amygdala, the emotional center of the brain. Thus, this study utilized a pre-clinical mouse model of CA/CPR to characterize amygdala dysfunction that arises from GCI. We found a male-specific deficit in associative learning and memory that corresponds with a circuit specific LTP deficit, which arises from elevated calcium signaling in dendritic spines. Thus, this study provides valuable information and rationale for extended follow up of CA/CPR survivors to identify and treat the development of GCI-induced affective disorders.
TiDHy: Timescale Demixing via Hypernetworks to learn simultaneous dynamics from mixed observations
Authors: Abe Elliott T. T. , Brunton Bingni W.
Published: January 2025

Neural activity and behavior arise from multiple concurrent time-varying systems, including neuromodulation, neural state, and history; however, most current approaches model these data as one set of dynamics with a single timescale. Here we developTimescaleDemixing viaHypernetworks (TiDHy) as a new computational method to model spatiotemporal data, decomposing them into multiple simultaneous latent dynamical systems that may span orders-of-magnitude different timescales. Specifically, we train a hyper-network to dynamically reweigh linear combinations of latent dynamics. This approach enables accurate data reconstruction, converges to true latent dynamics, and captures multiple timescales of variation. We first demonstrate that TiDHy can demix dynamics and timescales from synthetic data comprising multiple independent switching linear dynamical systems, even when the observations are mixed. Next, with a simulated locomotion behavior dataset, we show that TiDHy accurately captures both the fast dynamics of movement kinematics and the slow dynamics of changing terrains. Finally, in an open-source multi-animal social behavior dataset, we show that the keypoint trajectory dynamics extracted with TiDHy can be used to accurately identify social behaviors of multiple mice. Taken together, TiDHy is a powerful new algorithm for demixing simultaneous latent dynamical systems with applications to diverse computational domains.
Unraveling latent cognitive, metacognitive, strategic, and affective processes underlying children’s problem-solving using Bayesian cognitive modeling
Authors: Mistry Percy K , Chang Hyesang , El-Said Dawlat , Menon Vinod
Published: January 2025

Children exhibit remarkable variability in their mathematical problem-solving abilities, yet the cognitive, metacognitive and affective mechanisms underlying these individual differences remain poorly understood. We developed a novel Bayesian model of arithmetic problem-solving (BMAPS) to uncover the latent processes governing children’s arithmetic strategy choice and efficiency. BMAPS inferred cognitive parameters related to strategy execution and metacognitive parameters related to strategy selection, revealing key mechanisms of adaptive problem solving. BMAPS parameters collectively explained individual differences in problem- solving performance, predicted longitudinal gains in arithmetic fluency and mathematical reasoning, and mediated the effects of anxiety and attitudes on performance. Clustering analyses using BMAPS parameters revealed distinct profiles of strategy use, metacognitive efficiency, and developmental change. By quantifying the fine-grained dynamics of strategy selection and execution and their relation to affective factors and academic outcomes, BMAPS provides new insights into the cognitive and metacognitive underpinnings of children’s mathematical learning. This work advances powerful computational methods for uncovering latent mechanisms of complex cognition in children.
Fast, flexible analysis of differences in cellular composition with crumblr
Authors: Hoffman Gabriel E. , Roussos Panos
Published: January 2025

Changes in cell type composition play an important role in human health and disease. Recent advances in single-cell technology have enabled the measurement of cell type composition at increasing cell lineage resolution across large cohorts of individuals. Yet this raises new challenges for statistical analysis of these compositional data to identify changes in cell type frequency. We introducecrumblr(DiseaseNeurogenomics.github.io/crumblr), a scalable statistical method for analyzing count ratio data using precision-weighted linear mixed models incorporating random effects for complex study designs. Uniquely,crumblrperforms statistical testing at multiple levels of the cell lineage hierarchy using a multivariate approach to increase power over tests of one cell type. In simulations,crumblrincreases power compared to existing methods while controlling the false positive rate. We demonstrate the application ofcrumblrto published single-cell RNA-seq datasets for aging, tuberculosis infection in T cells, bone metastases from prostate cancer, and SARS-CoV-2 infection.
Individual-specific effects of transcranial electrical stimulation on 40-Hz auditory steady-state responses
Authors: Mockevičius Aurimas , Wang Xiaojuan , Bjekić Jovana , Filipović Saša R. , Griškova-Bulanova Inga
Published: January 2025

Although transcranial electrical stimulation (tES) has shown positive behavioral outcomes in neuropsychiatric disorders, evidence has been mixed thus far. Therefore, the possibility of tracking brain activity changes following tES via neurophysiological markers would benefit a better understanding of tES effects and the future development of tES protocols. One promising marker is the auditory steady-state response (ASSR), an externally controlled oscillatory brain activity, typically at 40 Hz, evoked by a periodic auditory stimulus. In the present study, we aimed to test the offline effects of different types of tES on 40-Hz ASSR. Participants underwent four conditions of tES which was applied over the left posterior parietal cortex: transcranial direct current (tDCS), transcranial alternating current (tACS), oscillatory transcranial direct current (otDCS) and sham stimulation. Individually determined theta frequency was delivered in the tACS and otDCS protocols. Immediately following the tES application, electroencephalogram (EEG) was recorded during 40-Hz auditory click stimulation. The analysis of time-frequency data from 29 participants showed that phase-locking and amplitude of 40-Hz ASSR did not differ among tES conditions. However, baseline ASSR (during sham stimulation) had a significant negative correlation with change in ASSR relative to sham (tES – sham) as well as a positive correlation with the magnitude of change (|tES – sham|) following each tES protocol. The results suggest that tES effects on 40-Hz ASSR may be individual-specific and likely depend on the baseline neuronal state. The findings encourage future research to focus on individual factors that may contribute to tES outcomes.
DECIPHERING THE DARK SIDE OF HISTONE ADP-RIBOSYLATION: WHAT STRUCTURAL FEATURES OF DAMAGED NUCLEOSOME REGULATE THE ACTIVITIES OF PARP1 AND PARP2
Authors: Tatyana A. Kurgina , Nina A. Moor , Mikhail M. Kutuzov , Anton V. Endutkin , Olga I. Lavrik
Published: January 2025

Poly(ADP-ribose) polymerases are critical enzymes contributing to regulation of numerous cellular processes, including DNA repair. Within the PARP family, PARP1 and PARP2 primarily facilitate PARylation in the nucleus, particularly responding to genotoxic stress. The activity of PARPs is influenced by the nature of DNA damage and multiple protein partners, with HPF1 being the important one. Forming a joint active site with PARP1 (PARP2), HPF1 contributes to histone PARylation and following chromatin remodelling during genotoxic stress events. This study elucidates interrelation between the presence and location of a one-nucleotide gap within the nucleosome core particle (NCP) and PARP activities in automodification and heteromodification of histones. Utilizing a combination of classical biochemical methods with fluorescence-based technique and a single-molecule mass photometry approach, we have shown that the NCP architecture impacts the efficiency and pattern of histone ADP-ribosylation and binding to the histones-associated damaged DNA more significantly for PARP2 than for PARP1. Analysis based on existing studies of HPF1-dependent ADP-ribosylome and NCP structural dynamics allows to suggest that the DNA damage location and the conformational flexibility of histone tails modulated by post-translational modifications are crucial for delineating the distinct roles of PARP1 and PARP2 during genotoxic stress responses.

GRAPHICAL ABSTRACT
H-NS is a conserved repressor of the type VI secretion system inVibrio fischeri
Authors: Speare Lauren , Pavelsky Morgan , Jackson Aundre , Septer Alecia N.
Published: January 2025

The type VI secretion system (T6SS) is a broadly distributed interbacterial weapon found in both beneficial and pathogenic bacteria and can enhance a microbe’s ability to colonize a host.Vibrio fischeriis a beneficial symbiont of fish and squid and a model organism for T6SS function, which is activated in high-viscosity conditions. Previously, we isolated anhnsmutant in a transposon screen to identify regulators of the T6SS in the fish symbiontV. fischeriMJ11. Thehnsgene encodes the DNA-binding protein, H-NS, a conserved global regulator of gene expression that aids in adaptation to changing environments. Quantitative transcriptomes of thehnsmutant and parent strains grown in liquid or hydrogel media revealedhnsis required for the global transcriptional changes that occur during transition from lower to higher viscosity conditions. Furthermore, T6SS gene transcripts are more abundant in thehnsmutant in both conditions, suggesting H-NS represses T6SS in the parent. Single-cell fluorescence microscopy confirmedhnsmutant cells make more T6SS weapons in both liquid and hydrogel medium, where thehnsmutant is more proficient at killing a competitor strain, compared to the wild-type parent. Finally, disrupting thehnsgene in additional light organ isolates resulted in a similar derepression of T6SS, indicating H-NS is a conserved repressor of this interbacterial weapon. This work furthers our understanding of the role of H-NS as a global regulator during environmental shifts in a host-associated bacterial symbiont and expands the list of species where H-NS represses T6SS to includeV. fischeri.
Major antigenic differences inAeromonas salmonicidaisolates correlate with the emergence of a new strain causing furunculosis in Chilean salmon farms
Authors: Mancilla Marcos , Ojeda Adriana , Yuivar Yassef , Grandón Maritza , Grothusen Horst , Oyarzún Marcela , Bisquertt Alejandro , Ugalde Juan A. , Fuentes Francisco , Ibarra Pablo , Bustos Patricio
Published: January 2025

Aeromonas salmonicidais the etiological agent of furunculosis, a septicemic disease with high mortality rates affecting salmonids and other teleost species worldwide. Reviewing molecular diagnostic protocols for routine diagnostics, we realized that the amplification of thevapAtarget gene failed in some cases of furunculosis. Therefore, we hypothesized that the emergence of a new strain may be involved in recent outbreaks. In this work, we demonstrate that thevapAlocus is absent in the new strain, which explains why it lacks the major membrane component VapA protein, a critical virulence factor. In addition, we found that thevapA-absent strain differs from its counterparts in outer membrane protein and lipopolysaccharide profiles, suggesting profound changes at the membrane structure level and in antigenic properties. These features along with sequence analysis information allowed us to infer that a complex genomic rearrangement, probably an indel encompassing the entirevapAlocus, gave rise to this membrane phenotype. Although the causes for pathogen evolution and emergence were not fully elucidated, our results strongly suggest that thevapA-absent strain is responsible for a raising proportion of recent furunculosis cases, and that it may be related to a less virulent disease and a low serological response upon vaccination with theA. salmonicidaantigen formulation currently used in Chile.
T7 RNA polymerase-based gene expression from a transcriptionally silent rDNA spacer in the endosymbiont-harboring trypanosomatidAngomonas deanei
Authors: Kröninger Lena , Maurya Anay K. , Stiebeling Christian , Stirba Florian P. , Kim Zio , Nowack Eva C. M.
Published: January 2025

Eukaryotic life has been shaped fundamentally by the integration of bacterial endosymbionts. The trypanosomatidAngomonas deaneithat contains a β-proteobacterial endosymbiont, represents an emerging model to elucidate initial steps in symbiont integration. Although the repertoire of genetic tools forA. deaneiis growing, no conditional gene expression system is available yet, which would be key for the functional characterization of essential or expression of toxic proteins. Development of a conditional expression system based on endogenous RNA polymerase II (POLII) is hampered by the absence of information on transcription signals inA. deaneias well as the unusual genetic system used in the Trypanosomatidae that relies on read-through transcription. This mode of transcription can result in polar effects when manipulating expression of genes in their endogenous loci. Finally, only few resistance markers are available forA. deaneiyet, restricting the number of genetic modifications that can be introduced into one strain. To increase the range of possible genetic manipulations inA. deanei, and in particular, build the base for a conditional expression system that does not interfere with the endogenous gene expression machinery, here we (i) implemented two new drug resistance markers, (ii) identified the spacer upstream of the rDNA array on chromosome 13 as transcriptionally silent genomic locus, and (iii) used this locus for engineering an ectopic expression system that depends on the T7 RNA polymerase expressed from the δ-amastin locus. We show that transgene expression in this system is independent of the activity of endogenous RNA polymerases, reaches expression levels similar to the previously described POLII-dependent expression from the γ-amastin locus, and can be applied for studying endosymbiosis. In sum, the new tools expand the possibilities for genetic manipulations ofA. deaneiand provide a solid base for the development of an ectopic conditional expression system.
Regulation of brassinosteroid signaling through Arabidopsis transcription factor TCP8 by a conserved post-translational mechanism
Authors: Spears Benjamin J. , Magnabosco Samuel A. , Mozal Raegan , Beauford Nyle M. , Baker Noah C. , Voeglie Quinn , Gassmann Walter
Published: January 2025

The ability of plants to respond to changing environmental conditions is dependent on their capacities to produce fast, transient, and reversible changes to stress-responsive gene expression profiles. Post-translation modification of transcription factors has been identified as a contributing mechanism to these responses but has yet to be explored mechanistically in the TCPs, a plant-specific TF family known to be broadly involved in phytohormone signaling governing biotic and abiotic stress responses. Here, we use a recombinant expression system and proteomic approach to identify the specific residues at which AtTCP8 is covalently modified by the small peptide SUMO and demonstrate that loss of key lysine residues abolishes modification of the TF. We validate these observations by demonstrating the failure of a sumoylation-site-deficient AtTCP8 mutant to complement a knowntcp8BR signaling deficiency phenotype natively inArabidopsisand reduced transcriptional activity of the protein at a known regulatory target promoter. Further, we show that class I TCP orthologs in the model non-vascular plantPhyscomitrium patensare sumoylated as well in our system, a novel finding for TFs in this organism. These data support a conserved model for post-translational regulation by SUMO of phytohormone-responsive gene expression between vascular and non-vascular plants.
Deuterium labeling enables proteome wide turnover kinetics analysis in cell culture
Authors: Alamillo Lorena , Ng Dominic C. M. , Currie Jordan , Black Alexander , Pandi Boomathi , Manda Vyshnavi , Pavelka Jay , Schaal Peyton , Travers Joshua G. , McKinsey Timothy A. , Lam Maggie P. Y. , Lau Edward
Published: January 2025

The half-life of proteins is tightly regulated and underlies many cellular processes. It remains unclear the extent to which proteins are dynamically synthesized and degraded in different cell types and cell states. We introduce an improved D2O labeling workflow and apply it to examine the landscape of protein turnover in pluripotent and differentiating human induced pluripotent stem cells (hiPSC). The majority of hiPSC proteins show minimal turnover beyond cell doubling rates, but we also identify over 100 new fast-turnover proteins not previously described as short-lived. These include proteins that function in cell division and cell cycle checkpoints, that are enriched in APC/C and SPOP degrons, and that are depleted upon pluripotency exit. Differentiation rapidly shifts the set of fast-turnover proteins toward including RNA binding and splicing proteins. The ability to identify fast-turnover proteins in different cell cultures also facilitates secretome analysis, as exemplified by studies of hiPSC-derived cardiac myocytes and primary human cardiac fibroblasts. The presented workflow is broadly applicable to protein turnover studies in diverse primary, pluripotent, and transformed cells.
A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma
Authors: Dost Antonella F.M. , Balážová Katarína , Casellas Carla Pou , van Rooijen Lisanne M. , Epskamp Wisse , van Son Gijs J.F. , van de Wetering Willine J. , Lopez-Iglesias Carmen , Begthel Harry , Peters Peter J. , Smakman Niels , van Es Johan. H. , Clevers Hans
Published: January 2025

Chronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we describe a feeder- and serum-free primary adult human organoid model to investigate how inflammation influences alveolar regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an alveolar type 2 (AT2) maturation protocol enhances surfactant production and supports tubular myelin formation. Introducing a LATS inhibitor to the expansion condition induces alveolar type 1 (AT1) differentiation while maintaining AT2 cells. Using this platform, we find that interferon-gamma exerts cytotoxic effects on AT1 cells while promoting the growth of regenerating AT2 cells, illustrating how a single inflammatory stimulus can have divergent effects on alveolar epithelial cell types. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies, aimed to identify strategies to enhance alveolar regeneration.
Is efficiency of protein incorporations governed by membrane properties? Anα-synuclein and ceramide-1-phosphate investigation
Authors: Drabik Dominik , Hinc Piotr , Cierluk Karolina , Czogalla Aleksander
Published: January 2025

In protein-membrane interactions membranes provide an environment that enables proteins to fulfill multiple functions. Yet our knowledge about specificity of protein-membrane interactions is not sufficient. It is our hipothesis that this specificity is governed to a large extend by the properties of membrane itself. This study investigates the protein-membrane interactions in the case ofα-synuclein (αS) and ceramide-1-phosphate (C1P) enriched membranes. The interactions betweenαS and lipids were reported to be governed by various factors, including lipid composition, membrane curvature, charge and fluidity. On the other hand, C1P is anionic lipid and the shape of its molecule is similar to that of PA, which was reported to strongly interact withαS. There are three main aspect of this work. First of all interactions betweenαS and C1P enriched membranes is investigated using microscale thermophoresis. Secondly, systematic characterization of membrane systems is performed using bothin vitroandin silicotechniques. Eventually, principal component analysis and multiple linear regression are used to determine phenomenological dependency of those interactions in function of membrane properties.
Molecular evolution and diversity of isomerase–reductase operons involved in bacterial metabolism of glycosaminoglycans
Authors: Nishimura Yu , Okumura Kenji , Oiki Sayoko , Ogura Kohei , Hashimoto Wataru
Published: January 2025

Glycosaminoglycans (GAGs), comprising uronic acids and amino sugars, are widely distributed in human tissues such as the intestine and oral cavity. Various bacteria colonize these tissues by assimilating GAGs. 4-Deoxy-L-threo-5-hexosulose uronate (DHU) is produced during the degradation of GAGs. Pectin, abundant in plants, is also degraded into DHU. DHU is metabolized in a stepwise manner by the isomerase KduI or DhuI, followed by the reductase KduD or DhuD. Previous studies have shown that the two genes encoding isomerase and reductase (kduI-kduDanddhuD-dhuI, respectively) are designated in an operon. Therefore, it was believed thatdhuD-dhuIandkduI-kduDoperons evolved independently. Nevertheless, the discovery of a hybridkduI-dhuDoperon raised questions regarding the evolution of these operons. This study was conducted to investigate the factors driving the diversity of operons through a pan-genomic phylogenetic analysis across 3550 bacterial strains. Seven types of DHU metabolism-related operons were identified. The phylum Bacteroidota possesses a hybrid-typekduI-dhuDoperon rather thankduI-kduDorkduD-kduIoperon. The phylum Bacillota, but not Pseudomonadota or Bacteroidota, possesses thedhuD-dhuIoperon; however,dhuI-dhuDoperon was not detected in any bacterial strain. Although DHU is generated from the degradation of oligomerized GAG by an unsaturated glucuronyl hydrolase (UGL), the UGL gene was found in strains positive forkduD-kduI,dhuD-dhuI,kduI-dhuD, anddhuD-kduIoperons at high ratios, indicating that the acquisition of these operons is advantageous for colonization on human hosts. (230 words)

IMPORTANCE

Glycosaminoglycans (GAGs), crucial components of the extracellular matrix, play a vital role in host infection by pathogenic bacteria as well as in the colonization of the host by commensal bacteria.

The isomerases KduI and DhuI are nonhomologous isofunctional enzymes. ThedhuD-dhuIoperon is well conserved within certain phyla and appears to have a strong association with GAG metabolism. In contrast, thekduIsystem is more widely distributed across various species. Based on the possession ratios of genes encoding each enzyme that produces 4-deoxy-L-threo-5-hexosulose uronate, this study indicated that the substrates targeted by each metabolic system vary depending on the specific operon type.