bluuebunny/crossref_metadata_2025 huggingface dataset:
Mature solid teratoma of the uterine cervix: A rare case report and review of the literature
Authors: Li Minhua , Zheng Weiping
Published: March 2024

Rationale:

Most of the mature teratomas are found in the ovaries. Extragonadal teratomas are extremely rare. To date, there are only a handful of reports of uterine cervical teratomas documented in the English literature.

Patient concerns:

Herein we describe a rare case of a 40-year-old patient who was presented to our hospital for a cervical polypoid mass, which was finally confirmed to be mature solid teratoma in uterine cervix.

Diagnoses:

Histological examination of the polypoid mass was found to consist of ciliated pseudostratified columnar respiratory epithelium, intestinal epithelium and smooth muscle tissue, adipose tissue and mature glial component, epidermis, and skin adnexa. Meanwhile, no history of abortion, dilatation, and curettage was present in this patient, so implantation of fetal tissue was excluded. Therefore, we make a diagnosis of uterine cervical mature teratoma.

Interventions:

Tumorectomy was performed after discovering the cervical polypoid mass.

Outcomes:

The patient had been followed-up for next 3 months after surgery and no recurrence was documented until now.

Lessons:

Though teratomas of the uterine cervix are extremely rare, more attention should be paid on this rare but possible tumor for appropriate treatment in these patients.
Identification of serum microRNA alterations associated with long-term exercise-induced motor improvements in patients with Parkinson disease
Authors: Zhang Ziyi , Wu Ziwei , Hu Shenglan , He Miao
Published: March 2024

Background:

Long-term physical exercise has been shown to benefit patients with Parkinson disease (PD), but there is a lack of evidence regarding the underlying mechanism. A better understanding of how such benefits are induced by exercise might contribute to the development of therapeutic targets for improving the motor function in individuals with PD. The purpose of this study was therefore to investigate the possible association between exercise-induced motor improvements and the changes in serum microRNA (miRNA) levels of PD patients through small RNA sequencing for the first time.

Methods:

Thirteen PD patients completed our 3-month home-and-community-based exercise program, while 6 patients were assigned to the control group. Motor functions were measured, and small RNA sequencing with data analysis was performed on serum miRNAs both before and after the program. The results were further validated by quantitative real-time polymerase chain reaction. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were then conducted to determine the role of differentially expressed miRNAs.

Results:

The 3-month home-and-community-based exercise program induced significant motor improvements in PD patients in terms of Unified Parkinson’s Disease Rating Scale activities of daily living and Motor Subscale (P < .05), comfortable walking speed (P = .003), fast walking speed (P = .028), Six-Minute Walk Test (P = .004), Berg Balance Scale (P = .039), and Timed Up and Go (P = .002). A total of 11 miRNAs (10 upregulated and one downregulated) were identified to be remarkably differentially expressed after intervention in the exercise group, but not in the control group. The results of miRNA sequencing were further validated by quantitative real-time polymerase chain reaction. It was found that the targets of altered miRNAs were mostly enriched in the mitogen-activated protein kinase, Wnt, and Hippo signaling pathways and the GO annotations mainly included binding, catalytic activity, and transcription regulator activity.

Conclusion:

The exercise-induced motor improvements were possibly associated with changes in circulating miRNA levels in PD patients. These miRNAs, as well as the most enriched pathways and GO terms, may play a critical role in the mechanism of exercise-induced benefits in PD and serve as novel treatment targets for the disease, although further investigations are needed.
Single-cell transcriptomics reveals comprehensive microenvironment and highlights the dysfuntional state of NK cells in endometrioid carcinoma
Authors: Shi Wenjie , Wu Wuchen , Wang Jing , Meng Xianghong
Published: March 2024

Endometrioid endometrial cancer (EEC) is one of the most common gynecologic malignancies. The interaction between cancer cells and the cells in the tumor microenvironment (TME) plays a crucial role in determining disease progression and response to treatment. To better understand the diversity in the TME of ECC, we conducted a comprehensive analysis using single-cell RNA sequencing across 21 samples, including 16 ECC and 5 adjacent normal tissues. We primarily focused on tumor-infiltrating natural killer (NK) cells and their cell–cell interactions with other immune cell types. We identified a CD56dim_DNAJB1 NK cells subset, which had low cytotoxic capability and high stress levels, suggesting a dysfunctional state. This subset showed strong interactions with tumor-associated macrophages through several ligand–receptor pairs. Additionally, we observed that tumor-infiltrating LAMP3+ dendritic cells may inhibit CD8+ T cells or attract regulatory T cells to the tumor area. These dendritic cells also had impaired activation effects on NK cells within the TME. Our study provides valuable insights into the role of NK cells in cancer immunity and highlights the potential of targeting specific NK cell subsets for therapeutic purposes.
The effect of gestational diabetes mellitus on pregnancy outcomes in advanced primiparous women: A retrospective study
Authors: Yang Hong , Xiao Chanyun , Tu Jiahui
Published: March 2024

Gestational diabetes mellitus (GDM) could have a variable degree of adverse effects on pregnancy outcomes for both pregnant women and newborns. The purpose of the study was to explore the effect of GDM on pregnancy outcomes in advanced primiparous women. A total of 1076 advanced primiparous women were included between January 2020 and December 2022. All these women were divided into the GDM group (n = 434) and the non-GDM group (n = 642). Variables included baseline characteristics, maternal, and newborn outcomes were collected. The risk of each adverse outcome was analyzed by multivariate logistic regression models. The effect of blood glucose control on pregnancy outcomes was further analyzed among GDM women with good glycaemic control (n = 381) and poor glycaemic control (n = 53). Analysis of baseline characteristics demonstrated a significant difference in prepregnancy body mass index (median, IQR: 22.27 [20.58–24.44] vs 21.17 [19.53–22.86], P < .01) between the GDM group and the non-GDM group. A significantly higher incidence rate of adverse pregnancy outcomes was found in advanced primiparous women with GDM, such as polyhydramniosis, premature birth, low-birth weight, macrosomia, and neonatal intensive care unit admission (all P < .05). Compared with the non-GDM group, the risk of polyhydramniosis was nearly twice as high in the GDM group (adjusted odds ratio: 1.94, 95% confidence interval: 1.01–3.72, P = .04) after adjusted baseline characteristics. Among the GDM group, the women with poor glycaemic control showed a significantly higher incidence rate of polyhydramnios, hypertensive disorders of pregnancy, cesarean delivery, premature birth, low-birth weight, macrosomia, and neonatal intensive care unit admission was significant than the women with good glycaemic control (all P < .05). GDM was an independent risk factor for polyhydramnios in advanced primiparous women. At the same time, good glycaemic control in diabetics advanced primiparous women could reduce adverse pregnancy outcomes.
Recurrence of locally invasive retroperitoneal dedifferentiated liposarcoma shortly after surgery: A case report and literature review
Authors: Hu Xuelian , Han Bo , Yang Qin , Li Qixuan , Xiao Dongkai , Xu Xiaosong
Published: March 2024

Rationale:

Retroperitoneal dedifferentiated liposarcoma (RPDDL) is an uncommon malignancy, which often remains undetected for many years due to having adequate space in the retroperitoneal cavity and lacking clinical manifestations in the early stage of the disease. Surgical procedure is usually used as the first choice for treatment. However, it is prone to local recurrence after the operation, resulting in an unfavorable prognosis. Our aim is to draw useful lessons from the new case and provide some experience for management of the disease.

Patient concerns:

We describe a 55-year-old male patient who was admitted for a 3-week history of persistent dull ache of the left waist. A large mass of the left upper abdomen was palpated in physical examination. Moreover, the imaging examination revealed that the diameter of the mass was about 21 cm, and some adjacent vital organs were invaded, which brought great challenges to complete surgical resection.

Diagnosis:

The postoperative pathological results confirmed that the mass was RPDDL with invasion of the surrounding vital structures including pancreas, spleen, left adrenal gland, left kidney, and vasculature with tumor emboli.

Interventions:

Surgical resection of the mass was performed by our multidisciplinary team. The patient received chemotherapy 1 month after surgery.

Outcomes:

The effect of chemotherapy seemed to be unsatisfactory. Local multifocal recurrence of the tumor was considered about 2 months after surgery. Finally, he gave up any treatments and died of the disease.

Lessons:

Regular physical examination and ultrasound screening may detect the disease as early as possible, especially for high-risk group aged 60 to 70, which should be popularized. Incomplete resection, vascular invasion, and interruption of postoperative treatment may lead to an unfavorable prognosis. Therefore, we think that patients with the disease may benefit from complete surgical resection and uninterrupted adjuvant therapy.
Congenital hemivertebrae combined with situs inversus totalis: A rare case report
Authors: Guo Zheng , Li Donglai , Zang Xuehui
Published: March 2024

Rationale:

Situs inversus totalis is a rare malposition of organs that typically involves lesions in the respiratory, circulatory, or urinary systems. Cases of congenital hemivertebrae combined with situs inversus totalis are extremely rare and have limited reports.

Patient concerns:

We report a 2.5 years old girl with 2 congenital hemipyramids and complete visceral inversion who ultimately underwent hemilaminectomy.

Diagnosis:

Congenital hemivertebrae combined with situs inversus totalis.

Intervention:

The patient underwent hemilaminectomy.

Outcomes:

The spinal deformity was corrected.

Lessons:

For patient with spinal deformities combined with situs inversus totalis, surgery can be an effective treatment method. But we also need to be vigilant about the dysfunction of various systems.
Sarcomatoid hepatocellular carcinoma: A case report and review of the literature
Authors: Hu Chengyin , Zhao Mingwei , Wei Qiang , Chen Zhuo , Zhao Baolei
Published: March 2024

Rationale:

Sarcomatoid hepatocellular carcinoma (SHC) is a rare malignant tumor composed of both carcinoma and sarcoma components. It has atypical clinical symptoms and a high degree of malignancy, with rapid progression and a poor prognosis.

Patient concerns:

A 63-year-old female patient was admitted to our hospital with a chief complaint of fatigue present for more than 1 month and fever for 10 days.

Diagnoses:

This patient underwent an upper abdominal MRI plain scan and enhanced scan showed a solid tumor in the right lobe of the liver, with a size of approximately 4.7 cm × 4.0 cm × 6.5 cm, present as low signal on T1WI, slightly high signal on T2WI, and heterogeneous high signal on DWI. Multi-phase dynamic contrast-enhanced MR scan showed significant enhancement in the arterial phase and low enhancement in the portal and delayed phases. The pathology showed the tumor cells to be positive for cytokeratin (CK), Vimentin, EMA, CD34, cyclinD1, negative for CK8, CK19, CK20, SMA, Desmin, S-100, CD117, Dog-1, Hepar-1, SOX-10 and ALK, and Ki-67 approximately 50%, which confirmed the diagnosis of SHC.

Interventions:

Laparoscopic right posterior lobe of liver resection was conducted, and the postoperative pathology revealed the presence of SHC.

Outcomes:

The patient was discharged 9 days after the surgery without any complications. There has been no evidence of recurrence at the 1 month, however bilateral pleural metastases appeared during the follow-up 3 months after surgery.

Lessons:

SHC is a rare and aggressive liver cancer. So far, there is still a lack of effective therapeutic strategy, and the prognosis was dismal even though patients received radical surgical resection.
Opioid Use Among Children and Adults With Sickle Cell Disease in North Carolina Medicaid Enrollees in the Era of Opioid Harm Reduction
Authors: Crego Nancy , Douglas Christian , Bonnabeau Emily , Eason Kern , Earls Marian , Tanabe Paula , Shah Nirmish
Published: March 2024

Adults and children with sickle cell disease (SCD) are predominantly African American, with pain-related health disparities. We examined opioid prescription fill patterns in adults and children with SCD and compared factors associated with fills in North Carolina Medicaid enrollees. Our retrospective cohort study included 955 enrollees diagnosed with SCD having at least one opioid fill. Associations were measured between two cohorts (12 and 24 mo of continuous enrollment) for the following characteristics: sex, age, enrollee residence, hydroxyurea adherence, comanagement, enrollment in Community Care North Carolina, prescription for short versus short and long-acting opioids, and emergency department reliance. The majority of individuals did not have an opioid claim over a 12 or 24-month period. Claims increased at ages 10 to 17, peaking at ages 18 to 30. The increased number of claims was associated with the following factors: increasing age, male, short versus long-acting opioids, and Medicaid enrollment for 24 versus 12 months. Community Care North Carolina enrollees in the 12-month cohort had higher opioid days of supply per month; the inverse was true of the 24-month cohort.
The Rhinoplasty Rosetta Stone: Using Rasch Analysis to Create and Validate Crosswalks between the NOSE and the SCHNOS Functional Subscale
Authors: van Zijl Floris V. W. J. , Declau Frank , Rizopoulos Dimitris , Datema Frank R.
Published: March 2024

Background:

The Nasal Obstruction Symptom Evaluation (NOSE) and the Functional subscale of the Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS-O) are widely used patient-reported outcome measures to measure functional outcomes of rhinoplasty. However, as different instruments produce scores on different metrics, results of these instruments cannot be linked directly, thus hindering comparison and aggregating of rhinoplasty outcome data from practices using either instrument. The aim of this study was to develop and validate crosswalks between the NOSE and the SCHNOS-O.

Methods:

In a sample of 552 rhinoplasty patients who completed both instruments, the NOSE and SCHNOS-O scales were co-calibrated onto a common interval-scaled metric using Rasch analysis. Separate Rasch models were run per instrument, and the latent constructs were estimated using the calibrated item parameters. By anchoring original patient-reported outcome measure scores of both instruments to this Rasch computed measurement scale, the scores of both instruments were linked. A second independent sample was used to validate the created crosswalks.

Results:

Total scores on the NOSE and SCHNOS-O were strongly correlated. The Rasch-based co-calibration of the NOSE and SCHNOS-O items resulted in a model that adequately fitted the data. Back-and-forth crosswalk tables were created from the NOSE to the SCHNOS-O. For patients with moderate nasal obstruction, predicted SCHNOS-O scores were slightly higher for a given level of the NOSE. Intraclass correlation coefficients between predicted and actual scores were 0.93 for both directions, indicating adequate agreement for group-level comparisons.

Conclusions:

This study developed and validated Rasch-based crosswalks from the NOSE to the SCHNOS-O and vice versa. The provided crosswalks enhance comparison and harmonization of functional rhinoplasty outcomes.
A National Analysis of Targeted Muscle Reinnervation following Major Upper Extremity Amputation
Authors: Valentine Lauren , Weidman Allan A. , Foppiani Jose , Hernandez Alvarez Angelica , Kim Erin , Hassell Natalie E. , Elmer Nicholas , Engmann Toni F. , Lin Samuel J. , Dowlatshahi Sammy
Published: March 2024

Background:

Postamputation pain is a debilitating sequela of upper extremity (UE) amputation. Targeted muscle reinnervation (TMR) is a relatively novel treatment that can help prevent pain and improve quality of life. The purpose of this study was to evaluate national trends in the application of immediate TMR following UE amputations.

Methods:

An analysis of the Nationwide Inpatient Sample database was conducted from 2016 to 2019. International Classification of Diseases, 10th Revision, codes were used to identify encounters involving UE amputation with and without TMR. Nationwide Inpatient Sample weights were used to estimate national estimates of incidence. Patient-specific and hospital-specific factors were analyzed to assess associations with use of TMR.

Results:

A total of 8945 weighted encounters underwent UE amputation, and of those, only 310 (3.5%) received TMR. The majority of TMR occurred in urban hospitals (>95%). Younger patients (47 years versus 54 years; P = 0.008) and patients located in New England were significantly more likely to undergo TMR. There was no difference in total cost of hospitalization among patients who underwent TMR ($55,241.0 versus $59,027.8; P = 0.683) but significantly shorter lengths of hospital stay when undergoing TMR versus other management (10.6 days versus 14.8 days; P = 0.012).

Conclusions:

TMR has purported benefits of pain reduction, neuroma prevention, and increased prosthetic control. Access to this beneficial procedure following UE amputation varies by demographics and geographic region. Given that TMR has not been shown to increase cost while simultaneously decreasing patient length of stay, increased efforts to incorporate this procedure into training and practice will help to ensure equitable care for amputation patients.
Smoking Primes the Metabolomic Response in Trauma
Authors: Gallagher Lauren T. , Erickson Christopher , D’Alessandro Angelo , Schaid Terry , Thielen Otto , Hallas William , Mitra Sanchayita , Stafford Preston , Moore Ernest E. , Silliman Christopher C. , Calfee Carolyn S. , Cohen Mitchell J.
Published: March 2024

Introduction

Smoking is a public health threat due to its well described link to increased oxidative stress-related diseases including peripheral vascular disease and coronary artery disease. Tobacco use has been linked to risk of inpatient trauma morbidity including acute respiratory distress syndrome, however its mechanistic effect on comprehensive metabolic heterogeneity has yet to be examined.

Methods

Plasma was obtained on arrival from injured patients at a Level 1 Trauma Center and analyzed with modern mass spectrometry-based metabolomics. Patients were stratified by non-smoker, passive smoker and active smoker by lower, inter-quartile and upper quartile ranges of cotinine intensity peaks. Patients were sub-stratified by High Injury/High Shock (Injury Severity Score ≥ 15, Base Excess<-6) and compared to healthy controls. P-value <0.05 following FDR correction of t-test was considered significant.

Results

48 patients with High Injury/High Shock (7 (15%) non-smokers, 25 (52%) passive smokers and 16 (33%) active smokers) and 95 healthy patients who served as controls (30 (32%) non-smokers, 43 (45%) passive smokers and 22 (23%) active smokers) were included. Elevated metabolites in our controls who were active smokers include enrichment in chronic inflammatory and oxidative processes. Elevated metabolites in active smokers in high injury/high shock include enrichment in the malate-aspartate shuttle, tyrosine metabolism, carnitine synthesis, and oxidation of very long-chain fatty acids.

Conclusions

Smoking promotes a state of oxidative stress leading to mitochondrial dysfunction which is additive to the inflammatory milieu of trauma. Smoking is associated with impaired mitochondrial substrate utilization of long-chain fatty acids, aspartate and tyrosine all of which accentuate oxidative stress following injury. This altered expression represents an ideal target for therapies to reduce oxidative damage toward the goal of personalized treatment of trauma patients.

Level of Evidence

Level III, Prognostic/Epidemiological
Impact of Preformed Donor-specific Antibodies in Comparison to ABO Incompatibility in Living Donor Liver Transplantation: A Propensity Score–Matched Analysis
Authors: Kim Jiyoung , Hong Suk Kyun , Kim Jae-Yoon , Lee Jaewon , Choi Hyun Hwa , Kim Minseob , Kim Youngjin , Hong Su young , Lee Jeong-Moo , Choi YoungRok , Yi Nam-Joon , Lee Kwang-Woong , Suh Kyung-Suk
Published: March 2024

Background.

Immunological factors play a pivotal role in the outcomes of solid organ transplantation. We aimed to elucidate the effects of donor-specific antibodies (DSAs) and ABO compatibility on living donor liver transplantation (LDLT) outcomes.

Methods.

A retrospective analysis was conducted on 584 LDLT recipients from 2015 to 2020. The recipients were stratified into 3 groups: ABO-compatible recipients without DSAs (group 1), ABO-compatible recipients with DSAs (group 2), and ABO-incompatible recipients without DSAs (group 3). Propensity score matching was used for balanced comparisons.

Results.

In the matched comparisons, group 2 exhibited a higher incidence of T cell–mediated rejection compared with group 1 (22.7% versus 4.5%, P = 0.030). Despite this, the 5-y survival rates were similar between groups 1 and 2 (81.6% versus 95.5%, P = 0.085). Group 3, in comparison with group 1, showed elevated rates of cytomegalovirus infection (23.2% versus 7.3%, P = 0.008), T cell–mediated rejection (28.0% versus 7.3%, P = 0.001), and antibody-mediated rejection (13.4% versus 0%, P = 0.001). However, the survival rates were comparable between group 3 and group 1 (82.0% versus 86.5%, P = 0.220, respectively). Comparisons between group 2 and group 3 did not reveal significant differences in postoperative outcomes or survival rates (P > 0.05).

Conclusions.

DSA positivity and ABO incompatibility contribute to distinct posttransplant complications in LDLT. The integrated consideration of both factors in pretransplant assessment may enhance risk stratification and inform tailored interventions. Further research is required to corroborate these findings and provide mechanistic insights.
Optimizing ODE-derived Synthetic Data for Transfer Learning in Dynamical Biological Systems
Authors: Zabbarov Julian , Witzke Simon , Kleissl Maximilian , Iversen Pascal , Renard Bernhard Y. , Baum Katharina
Published: March 2024

Motivation

Successfully predicting the development of biological systems can lead to advances in various research fields, such as cellular biology and epidemiology. While machine learning has proven its capabilities in generalizing the underlying non-linear dynamics of such systems, unlocking its predictive power is often restrained by the limited availability of large, curated datasets. To supplement real-world data, informing machine learning by transfer learning with data simulated from ordinary differential equations has emerged as a promising solution. However, the success of this approach highly depends on the designed characteristics of the synthetic data.

Results

We optimize dataset characteristics such as size, diversity, and noise of ordinary differential equation-based synthetic time series datasets in three relevant and representative biological systems. To achieve this, we here, for the first time, present a framework to systematically evaluate the influence of such design choices on transfer learning performance in one place. We achieve a performance improvement of up to 92% in mean absolute error for our optimized simulation-based transfer learning compared to non-informed deep learning. We find a strong interdependency between dataset size and diversity effects. The optimal transfer learning setting heavily relies on real-world data characteristics as well as its coherence with the synthetic data’s dynamics, emphasizing the relevance of such a framework.

Availability and Implementation

The code is available athttps://github.com/DILiS-lab/opt-synthdata-4tl.
Inflammation induced Th17 cells synergize with the inflammation-trained microbiota to mediate host-resiliency against intestinal injury
Authors: Golob JL , Hou G , Swanson BJ , Bishu S , Grasberger H , El Zataari M , Lee A , Kao J , Kamada N , Bishu S
Published: March 2024

Background and Aims

Inflammation can generate pathogenic Th17 cells and cause a inflammatory dysbiosis. In the context of Inflammatory Bowel Disease (IBD) these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells (IECs). However, many models of IBD like T-cell transfer colitis and IL-10-/-mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammationcan also induce protective Th17 cells.

Methods

We subjected C57BL6, RAG1-/-or JH-/-mice to systemic or gastrointestinal (GI)Citrobacter rodentium(Cr). Mice were then subject to 2.5% dextran sodium sulfate to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, 16s sequencing and histology were used to assess parameters.

Results

Transient inflammation with GI but not systemicCrwas protective from subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue resident memory signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/-mice and cell trafficking inhibitors showed that inflammation induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cellsin situ.

Conclusion

Inflammation can generate protective Th17 cells which synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation induced Th17 tissue resident memory T cells are heterogenous and contain protective subsets.
PIM kinase control of CD8 T cell protein synthesis and cell trafficking
Authors: Marchingo Julia M , Spinelli Laura , Pathak Shalini , Cantrell Doreen A
Published: March 2024

Integration of a large network of kinase signalling pathways co-ordinates changes in the transcription, translation and metabolic events required for T cell activation and differentiation. The present study explores the role of the Serine/Threonine kinases PIM1 and PIM2 in controlling murine CD8 T lymphocyte antigen receptor-mediated activation and differentiation in response to the cytokines Interleukin 2 (IL-2) or IL-15. We show that PIM kinases are dispensable for the differentiation programs controlled by the antigen-receptor and IL-15. There is however a selective role for the PIM kinases in the context of IL-2 regulation of CD8 T cell fate. One key insight was that the PIM kinases controlled the migratory capabilities of effector CD8 T cells, withPim1/Pim2-deficient CD8 T cells unable to fully switch off the naïve T cell chemokine and adhesion receptor program during effector differentiation. PIM kinases were also needed for IL-2 to sustain high expression of the glucose transporters SLC2A1 and SLC2A3 and to maintain activity of the nutrient sensing kinase mTORc1. Strikingly, PIM kinases did not have a dominant impact on IL-2-driven transcriptional programs but rather selectively modulated protein synthesis to shape cytotoxic T cell proteomes. This study reveals a selective role of PIM kinases in IL-2 control of CD8 T cells and highlights how regulated changes in protein synthesis can impact T cell phenotypes.
Sex chromosome turnover in African annual killifishes of the genus Nothobranchius
Authors: Hospodarska Monika , Mora Pablo , Volenikova Anna Chung , Al-Rikabi Ahmed , Simanovsky Sergey A. , Pavlica Tomas , Altmanova Marie , Janeckova Karolina , Stundlova Jana , Tolar Nikolas , Jankasek Marek , Hirman Matyas , Liehr Thomas , Reichard Martin , Krysanov Eugene Yu. , Rab Petr , Englert Christoph , Nguyen Petr , Sember Alexandr
Published: March 2024

Sex chromosomes of teleost fishes often have low levels of differentiation and undergo frequent turnovers. Annual Nothobranchius killifishes comprise representatives with male-heterogametic XY or X1X2Y sex chromosome systems, scattered across their phylogeny, nested within species lacking cytologically detectable sex chromosomes. They thus provide a suitable system to study sex chromosome evolution and turnover. Here, we combined molecular cytogenetics and genomic analyses to examine several multiple sex chromosome systems in Nothobranchius spp. and their outgroup Fundulosoma thierryi. We used fluorescence in situ hybridization with three sex chromosome-specific painting probes and bacterial artificial chromosomes (BAC) bearing eight orthologues of genes found to be repeatedly co-opted as master sex determining (MSD) genes in fishes. Our results suggest at least four independent origins of sex chromosomes in the genus Nothobranchius. The synteny block carrying amhr2 gene was shared by X1X2Y systems of N. brieni, N. guentheri and N. lourensi, but the autosomal additions and the overall neo-Y chromosome structure differed among these species. On the other hand, gdf6 gene was localized to neo-Y of F. thierryi. None of the mapped MSD gene candidates seems to determine sex in N. ditte. We further sequenced genomes of F. thierryi female and N. guentheri male by long-read platforms and performed analyses of male and female Pool-seq data and coverage to delimit their non-recombining regions, determine degree of their differentiation, and thus complement the cytogenetic data in assessing potential MSD genes. We found low level of sex chromosomes differentiation in F. thierryi. In N. guentheri, however, we identified two distinct evolutionary strata on neo-Y. The amhr2 gene resides in the younger stratum and has low allelic variation, which questions its role in sex determination.
Does Haldane’s rule speciation within mimetic Poison frogs?
Authors: Lorioux-Chevalier Ugo , Chouteau Mathieu , Roland Alexandre-Benoit
Published: March 2024

To explain how populations with distinct warning signals coexist in close parapatry, we experimentally assessed intrinsic mechanisms acting as reproductive barriers within threeRanitomeyapoison-frog species. For all species, assortative mating did not occur, nor did a survival disadvantage for inter-population hybrids. However, inRanitomeya fantastica, these hybrids of the male sex are sterile, an outcome predicted by Haldane’s rule. Our results suggest a possible XY sex determinism inR. fantastica, and show that this process is associated with an extraordinary diversity, leading to speciation.

Graphical Abstract
Bridging polarities in metabolomics: Cross-ionization mode chemical similarity prediction between tandem mass spectra
Authors: de Jonge Niek F. , Chekmeneva Elena , Schmid Robin , Joas David , Truong Lem-Joe , van der Hooft Justin J.J. , Huber Florian
Published: March 2024

Mass spectrometry is a cornerstone of untargeted metabolomics, enabling the characterization of metabolites in both positive and negative ionization modes. However, comparisons across ionization modes have remained a substantial challenge due to the distinct fragmentation patterns produced by each polarity. To overcome this barrier, we present MS2DeepScore 2.0, a machine learning-based model to predict chemical similarity between mass fragmentation spectra, which works both between different and the same ionization modes. We demonstrate the utility of MS2DeepScore 2.0 in a human urine case study, where MS2DeepScore enabled cross-ionization mode molecular networking, enhancing data exploration and metabolite annotation. To ensure robustness, we have implemented a quality estimation method that flags spectra with low information content or those dissimilar to the training data, thereby minimizing false predictions. Altogether, MS2DeepScore 2.0 extends our current capabilities in organizing, exploring, and annotating untargeted metabolomics profiles.
Development of sound production inDanionella cerebrum
Authors: Groneberg Antonia H. , Dressler Lena E. , Kadobianskyi Mykola , Müller Julie , Judkewitz Benjamin
Published: March 2024

Acoustic signaling, integral to intraspecific communication and reproductive behavior, undergoes notable changes during an animal’s ontogenetic development. The onset and progression of this maturation in fish remains poorly understood. Here, we investigate the ontogeny of acoustic communication in the micro glassfishDanionella cerebrum(DC), one of the smallest known vertebrates and an emerging model organism in neuroscience. Adult DC males produce audible clicks that appear in sequences with a repetition rate of 60 or 120 Hz, caused by consecutive unilateral or alternating bilateral compressions, respectively. To investigate the maturation of this ability, we performed long-term sound recordings and morphological studies of the DC sound production apparatus throughout its ontogenetic development. We found that DC start producing clicks during the second month of their lives and continually increase their abundance and structured repetition over the course of the following one to two months. The sound production machinery, including specialized bone and cartilage structures, start to form in male DC after approximately four weeks and prior to full maturation of the reproductive organs. While the DC clicks increase in amplitude with age and body size, click repetition rates of 60 and 120 Hz are stable throughout development. This suggests a fully developed central pattern generator in juvenile males, yet a continued maturation of the drumming apparatus capable of creating louder sounds.
Estimation of Jacquard’s genetic identity coefficients with bi-allelic variants by constrained least-squares
Authors: Graffelman Jan , Weir Bruce S. , Goudet Jérôme
Published: March 2024

The Jacquard genetic identity coefficients are of fundamental importance in relatedness research. We address the estimation of these coefficients as well as other relatedness parameters that derive from them such as kinship and inbreeding coefficients using a concise matrix framework. Estimation of the Jacquard coefficients via likelihood methods and the expectation–maximization algorithm is computationally very demanding for large numbers of polymorphisms. We propose a constrained least squares approach to estimate the Jacquard coefficients. A simulation study shows constrained least squares achieves root-mean-squared errors that are comparable with those of the maximum likelihood approach, in particular when founder allele frequencies are unknown, while obtaining enormous computational savings.
Retinotopic biases in contextual feedback signals to V1 for object and scene processing
Authors: Bennett Matthew A. , Petro Lucy S. , Abbatecola Clement , Muckli Lars
Published: March 2024

Identifying the objects embedded in natural scenes relies on recurrent processing between lower and higher visual areas. How is cortical feedback information related to objects and scenes organised in lower visual areas? The spatial organisation of cortical feedback converging in early visual cortex during object and scene processing could be retinotopically specific as it is coded in V1, or object centred as coded in higher areas, or both. Here, we characterise object and scene-related feedback information to V1. Participants identified foreground objects or background scenes in images with occluded central and peripheral subsections, allowing us to isolate feedback activity to foveal and peripheral regions of V1. Using fMRI and multivoxel pattern classification, we found that feedback of object information is projected to foveal V1 cortex with increased detail during an object identification task. Background scene information is projected to both foveal and peripheral V1 but can be disrupted by a sufficiently demanding object discrimination task. We suggest that the feedback connections during scene perception project back to earlier visual areas an automatic sketch of occluded information to the predicted retinotopic location. In the case of a cognitive task however, feedback pathways project content to foveal retinotopic space, potentially for introspection, functioning as a cognitive active blackboard and not necessarily predicting the object’s location. This feedback architecture could reflect the internal mapping in V1 of the brain’s endogenous models of the visual environment that are used to predict perceptual inputs.
Human ancestry inference at scale, from genomic data
Authors: Warren René L , Coombe Lauren , Wong Johnathan , Kazemi Parham , Birol Inanc
Published: March 2024

Using an alignment-free single nucleotide variant prediction framework that leverages integrated variant call sets from the 1000 Genomes Project, we demonstrate accurate ancestry inference predictions on over 600 human genome sequencing datasets, including complete genomes, draft assemblies, and >280 independently-generated datasets. The method presented, ntRoot, infers super-population ancestry along an input human genome in 1h15m or less on 30X sequencing data, and will be an enabling technology for cohort studies.
Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function
Authors: Ono Kazuya , Jarysta Amandine , Hughes Natasha C. , Jukic Alma , Chang Hui Ho Vanessa , Deans Michael R. , Eatock Ruth Anne , Cullen Kathleen E. , Kindt Katie , Tarchini Basile
Published: March 2024

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs inGpr156mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast,gpr156zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity,Gpr156mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered – swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.
Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance toPlasmodiuminfection
Authors: Matteucci Kely C. , Assis Patricia A. , Hirako Isabella C. , Leite Nathalia P. S. , Pioto Franciele , Ojelabi Ogooluwa , Toller-Kawahisa Juliana E. , Costa Diego L. , Da Silva João S. , Alves-Filho José C. , Gazzinelli Ricardo T.
Published: March 2024

TNF has a dual effect inPlasmodiuminfection, bolstering the host’s immune defense while also triggering disease. Here, we show that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen as well as controlling parasitemia inP. chabaudi(Pc)-infected mice. We also demonstrate that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of HIF-1α, expression of glucose transporter GLUT1 and enhanced glycolysis in monocytic cells fromPc-infected mice. Importantly,Pc- infected iNOS-/-, TNFRΔLyz2andHIF-1αΔLyz2mice show impaired release of TNF and glycolysis in monocytes, together with increased parasitemia and disease tolerance. Together, our findings reveal that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior inPc-infected mice.
Non-invasive optoacoustic imaging visualizes exercise-induced dermal revascularization in obese mice
Authors: Huang Shan , He Hailong , Tom Robby Z. , Glasl Sarah , Anzenhofer Pia , Stiel Andre C. , Hofmann Susanna M. , Ntziachristos Vasilis
Published: March 2024

Microcirculatory dysfunction in dermal (dWAT) and subcutaneous white adipose tissue (scWAT) of obese humans may predict cardio-metabolic disease progression.In-vivovisualization and monitoring of microvascular remodeling in these tissues remains challenging. We compared performance of multi-spectral optoacoustic tomography (MSOT) and raster-scanning optoacoustic mesoscopy (RSOM) in visualizing lipid and hemoglobin contrast in scWAT and dWAT of diet-induced obese (DIO) mice undergoing voluntary wheel running. MSOT quantitatively visualized lipid and hemoglobin contrast in fat depots at early stages of DIO. RSOM precisely visualizes microvasculature with quantitative readouts of skin layer thickness and vascular density in dWAT and dermis. Combination of MSOT and RSOM resolved exercise-induced morphological changes in microvasculature density, tissue oxygen saturation, lipid and blood volume content in dWAT and scWAT. Combination of MSOT and RSOM precisely monitor microcirculatory dysfunction and intervention response in dWAT and scWAT of DIO mice. Our findings lay out the foundation for future clinical studies using optoacoustic-derived vascular readouts from adipose tissues as a biomarker for monitoring microcirculatory function in cardio-metabolic disease.
Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration
Authors: Xu Jishu , Hörner Michaela , Nagel Maike , Perhat Perwin , Korneck Milena , Noß Marvin , Hauser Stefan , Schöls Ludger , Admard Jakob , Casadei Nicolas , Schüle Rebecca
Published: March 2024

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzedKIF1C-knockout (KO)CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent inKIF1C-KOaxons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact ofKIF1Con the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.
Hemoglobin gene repertoire in teleost and cichlid fishes shaped by gene duplications and genome rearrangements
Authors: Omelchenko Dmytro , Bitja-Nyom Arnold Roger , Matschiner Michael , Malinsky Milan , Indermaur Adrian , Salzburger Walter , Bartoš Oldřich , Musilova Zuzana
Published: March 2024

Hemoglobin is a crucial element of the oxygen transport system in vertebrates. It exhibits remarkable gene diversity across teleost fishes, reflecting their evolutionary adaptations for thriving in various aquatic environments. In this study, we present the dynamic evolution of hemoglobin subunit genes based on a comparison of high quality long-read genome assemblies of 24 vertebrate species, including 16 teleosts (of which six are cichlids). Our findings indicate that teleost genomes contain between five (fugu) and 43 (salmon) hemoglobin genes, representing the largest hemoglobin gene repertoire among vertebrates. We find evidence that the ancestor of teleosts had at least four Hbα and three or four Hbβ subunit genes, and that the current gene diversity emerged during subsequent teleost radiation, driven primarily by (tandem) gene duplications, genome compaction, and rearrangement dynamics. We provide insights into the genomic organization of hemoglobin clusters, revealing the parallel origin of multiple clusters in tetrapods and in teleosts. Importantly, we show that the presence of paralogous rhbdf1 genes flanking both teleost hemoglobin clusters (LA and MN) supports the hypothesis for the origin of the LA cluster by rearrangement within teleosts, rather than by the teleost specific whole-genome duplication. We specifically focus on cichlid fishes, where adaptation to low oxygen environments has been shown to play roles in species diversification. Our analysis of six cichlid genomes, including thePungu maclarenifrom crater lake Barombi Mbo, for which we sequenced the representative genome, reveals 18 to 31 copies of the Hb genes, and elevated rates of non- synonymous substitutions compared to other teleosts. Overall, this work facilitates a deeper understanding of how hemoglobin genes contribute to the adaptive and diversification potential of teleosts.