bluuebunny/crossref_metadata_2025 huggingface dataset:
Caffeine improves systemic lupus erythematosus endothelial dysfunction by promoting endothelial progenitor cells survival
Authors: Orefice Valeria , Ceccarelli Fulvia , Barbati Cristiana , Buoncuore Giorgia , Pirone Carmelo , Alessandri Cristiano , Conti Fabrizio
Published: October 2024

Objective

We studied the role of caffeine intake on endothelial function in SLE by assessing its effect on circulating endothelial progenitor cells (EPCs) both ex vivo in SLE patients and in vitro in healthy donors (HD) treated with SLE sera.

Methods

We enrolled SLE patients without traditional cardiovascular risks factors. Caffeine intake was evaluated with a 7-day food frequency questionnaire. EPCs percentage was assessed by flow cytometry analysis and, subsequently, EPCs pooled from six HD were co-cultured with caffeine with and without SLE sera. After 7 days, we evaluated cells’ morphology and ability to form colonies, the percentage of apoptotic cells by flow cytometry analysis and the levels of autophagy and apoptotic markers by western blot. Finally, we performed a western blot analysis to assess the A2AR/SIRT3/AMPK pathway.

Results

We enrolled 31 SLE patients, and observed a positive correlation between caffeine intake and circulating EPCs percentage. HD EPCs treated with SLE sera and caffeine showed an improvement in morphology and in number of EPCs colony-forming units in comparison with those incubated without caffeine. Caffeine was able to restore autophagy and apoptotic markers in HD EPCs as before SLE sera treatment. Finally, caffeine treatment was able to significantly reduce A2AR levels, leading to an increase in protein levels of SIRT3 and subsequently AMPK phosphorylation.

Conclusions

Caffeine intake positively correlated with the percentage of circulating EPCs in SLE patients; moreover, caffeine in vitro treatment was able to improve EPC survival and vitality through the inhibition of apoptosis and the promotion of autophagy via A2AR/SIRT3/AMPK pathway.
Psychiatric comorbidity in Danish patients with narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia: a case–control study
Authors: Haubjerg Østerby Niels Christian , Baandrup Lone , Jennum Poul Jørgen
Published: October 2024

Study Objectives

To examine the difference in psychiatric comorbidity of Danish patients with Narcolepsy type 1 (NT1), Narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

Methods

Polysomnography (PSG), Multiple Sleep Latency Test (MSLT), and lumbar puncture were performed on 505 patients referred to a sleep clinic for diagnostic evaluation of hypersomnia. Diagnosis, clinical characteristics, electrophysiologic data, and cerebrospinal fluid hypocretin-1 (Csf-Hcrt-1) results were retrieved. Subsequently, the patients were identified in the Danish national health registers to collect information on psychiatric diagnoses and psychotropic medication use 10 years before the sleep disorder diagnosis. The prevalence of psychiatric comorbidities per hypersomnia group was compared to a 1:4 general population control group matched on age, gender, and educational level.

Results

A diagnosis of NT2 and IH was significantly associated with total psychiatric comorbidity compared to the matched controls but not NT1 (NT1: OR = 1.5; NT2: OR = 6.1; IH: OR = 5.2). NT1 was not significantly associated with any psychiatric disorder. NT2 was significantly associated with schizophrenia spectrum disorders (OR = 8.5), mood disorders (OR = 6.7), neurotic disorders (OR = 3.8), personality disorders (OR = 3.1), and behavioral and emotional disorders (OR = 4.3). IH was significantly associated with schizophrenia spectrum disorders (OR = 3.3), mood disorders (OR = 5.9), neurotic disorders (OR = 3.0), and behavioral and emotional disorders (OR = 4.0).

Conclusions

NT2 and IH had a close relationship to psychiatric disorders before diagnosis of their sleep disorder, while NT1 did not. This supports previous studies finding higher rates of psychiatric illness in patients with hypersomnia; however, it highlights the similarity between NT2 and IH. We believe this link to psychiatric disorders could play a role in the pathophysiology. Future studies evaluating the relation between hypersomnias of central origin and psychiatric diseases should include hypersomnia subclassifications to further the understanding of the differences in these disorders.
Does severity of the flatfoot deformity affect pain and mobility in adolescents with symptomatic flatfoot
Authors: William Matthew , Pereira Daniel E. , Torres-Izquierdo Beltran , Schaibley Claire , Hosseinzadeh Pooya
Published: October 2024

Flexible flatfoot is a prevalent pediatric condition, with some cases resulting in pain and mobility limitations necessitating surgical intervention such as calcaneal lengthening osteotomy (CLO). The relationship between flexible flatfoot severity, BMI, and symptomats remains unclear. The study aims to investigate the association between the severity of flexible flatfoot deformity and BMI with pain and mobility impairment in children undergoing CLO. A retrospective database of pediatric patients with symptomatic flexible flatfoot treated with CLO was analyzed. Preoperative pain and mobility were assessed using Patient Reported Outcome Measurement Information System (PROMIS) scores. The severity of flexible flatfoot was determined by weight-bearing anteroposterior and lateral talo-first metatarsal angles. We included 57 patients with an average age of 12.18 years. The average preoperative PROMIS pain score was 53.76, and the mobility score was 41.27. No significant relationship was found between the severity of deformity and PROMIS scores for pain. Similarly, obesity did not significantly affect pain or mobility scores. In children with symptomatic flexible flatfoot undergoing CLO, neither the severity of the deformity nor obesity significantly influenced preoperative pain and mobility as measured by PROMIS scores. These findings suggest that factors other than the severity of flexible flatfoot deformity and obesity may contribute to the symptoms in this patient population.

Level of evidence:

Level III.
Neonatal Outcomes Following Maternal Antepartum Extracorporeal Life Support
Authors: Seadler Benjamin D. , Johnson Ashanti , Donato Britton B. , Andrews Weston G. , Ramamurthi Adhitya , Ubert Adam , Durham Lucian A.
Published: October 2024

Cases of antepartum respiratory failure or cardiogenic shock treated successfully with extracorporeal life support (ECLS) with high rates of survival for both mother and fetus are well documented. In contrast, there is a paucity of literature on the outcomes of these neonates after delivery. We report a single-center retrospective study of all adult cases of antepartum ECLS from February 2015 to April 2023 with neonatal follow-up. Seven patients met inclusion criteria with a maternal age of 32.0±5.5 years (median ± interquartile range [IQR]), primarily due to respiratory failure in six (86%) patients, with ECLS initiation at 27.0±3.0 weeks gestation. All mothers and fetuses survived to delivery at a gestational age of 29.0±4.5 weeks. All neonates survived to discharge home with the most common comorbidities being prematurity in seven (100%) patients and bronchopulmonary dysplasia in three (43%). In a follow-up period of 1.4±1.2 years; four (57%) patients underwent formal neurodevelopmental testing and two (50%) had identified delays, both related to speech/language. These results suggest that children exposed to antenatal ECLS demonstrate high rates of survival without significant morbidity, but that follow-up for neurodevelopmental delays may be warranted.
Uterine Sarcoma or Degenerating Fibroid? Validating the New Consensus Magnetic Resonance Imaging Algorithm for Evaluating Atypical Uterine Masses
Authors: Horowitz Jeanne M. , Lopes Vendrami Camila , Velichko Yuri S. , Green-Walker Aja I. , Kelahan Linda C. , Jawahar Anugayathri , Barber Emma L. , Shanes Elisheva D. , Miller Frank H. , Recht Hannah S.
Published: October 2024

Objective

The aim of the study is to assess the validity of a recently published consensus magnetic resonance imaging (MRI) diagnostic algorithm for differentiating degenerating leiomyomas from uterine sarcomas and other atypical appearing uterine malignancies.

Methods

Atypical uterine masses on pelvic MRI were identified using a radiology report search engine and teaching files with the keywords “atypical leiomyoma,” “atypical fibroid,” and “sarcoma.” All cases were pathology-proven. Two radiologists blinded to clinical, surgical, and pathologic reports retrospectively and independently reviewed 40 pelvic MRI examinations dated 1/2007–9/2022 to determine whether the masses appeared benign or malignant, using the 2022 consensus atypical uterine mass flow chart. Imaging features assessed included intermediate/high signal intensity (SI) at T2-weighted imaging, high diffusion weighted imaging SI (equal or higher SI than endometrium or lymph nodes on high b value imaging), apparent diffusion coefficient (ADC) value ≤0.905 × 10−3 mm2/s, peritoneal metastases, and abnormal lymph nodes.

Results

Among the 40 atypical uterine mass cases reviewed, 24 masses were benign (22 leiomyomas, 1 adenomyoma, and 1 borderline ovarian tumor) and 16 masses were malignant (6 leiomyosarcomas, 6 carcinosarcomas, 2 endometrial stromal sarcomas, 1 high-grade adenosarcoma, and 1 low-grade uterine sarcoma). Sensitivity, specificity, positive predictive value, and negative predictive value of whether a mass was benign or malignant were 75%, 95.8%, 92.3%, and 85% for reader 1, and 81.2%, 91.7%, 86.7%, and 88% for reader 2, respectively. Interrater agreement was strong, with a kappa statistic of 0.89. When excluding nonleiomyosarcoma uterine malignancies, sensitivity and negative predictive value improved to 100%.

Conclusions

The new consensus pelvic MRI algorithm for evaluating atypical uterine masses has good specificity, sensitivity, positive predictive value, and negative predictive value for determining malignancy, particularly for uterine sarcomas that are leiomyosarcomas. However, if ADC value is near but not below 0.905 × 10−3 mm2/s, the mass may still be malignant, especially if a b value lower than 1000 is used. If the atypical uterine mass is predominantly endometrial, morphological features on T2 and postgadolinium sequences should guide suspicion, as some atypical appearing nonleiomyosarcoma uterine malignancies may have an ADC value greater than 0.905 × 10−3 mm2/s.
Three-dimensional Stereoscopic Evaluation and Quantitative Gray Scale Assessment of the Nasolabial Fold and Its Application in Injection Therapy
Authors: Xiaohui Long , Chunyan Huang , Qiming Zhao , Xin Wang , Weidong Ping
Published: October 2024

With the growing demand for aesthetic enhancements, particularly filler injections for nasolabial folds (NLFs), there is a need for more objective and quantitative assessment methods beyond the traditional subjective scales like the Wrinkle Severity Rating Scale (WSRS). This study introduces a novel evaluation method combining 3-dimensional (3D) imaging and grayscale analysis to objectively assess NLF severity and treatment outcomes. A total of 100 healthy participants (86 females, 14 males; mean age 41.85±11.53 years) were assessed using WSRS scores and quantitative 3D measurements. The results demonstrated a significant positive correlation between WSRS scores and gray values (r=0.985, P < 0.05). Significant differences in gray values and 3D linear measurements were observed across WSRS score groups, with high intra-rater reliability confirmed by intraclass correlation coefficients. In addition, 54 patients (mean age 42.9±8.9 y) with moderate to severe NLFs received hyaluronic acid injections. One month post-treatment, WSRS scores significantly decreased (from 3.74±0.45 to 1.63±0.59, P < 0.05), and significant improvements were observed in several 3D measurements. The average gray value also decreased significantly (P < 0.05), indicating a reduction in wrinkle depth. These findings were supported by representative photos showing patient satisfaction and no severe complications. This study validates the use of 3D imaging and grayscale analysis as reliable tools for objectively assessing NLF severity and monitoring treatment efficacy, potentially improving the precision and reliability of aesthetic evaluations in clinical practice.
Proportional Condylectomy for the Treatment of Unilateral Condylar Hyperplasia With Maloclussion: Role of Point-of-Care Manufacturing Surgical Guides and Intraoperative Computed Tomography to Avoid Secondary Orthognatic Surgery
Authors: Tousidonis Manuel , Navarro-Cuellar Carlos , Fariña Rodrigo
Published: October 2024

Condylar hyperplasia (CH) is a complex, usually unilateral pathology affecting the jaw, leading to facial asymmetry and malocclusion. Its etiology is unclear, with potential links to endocrine disorders, trauma, and genetic factors. Unilateral condylar hyperplasia (UCH) typically presents in young patients but can occur at any age. Common symptoms include progressive facial asymmetry, malocclusion, and temporomandibular joint dysfunction. Diagnostic imaging like single positron emission computed tomography helps assess condylar activity. Treatment aims to halt condylar growth and correct facial asymmetry, commonly through high condylectomy, which involves removing the upper 3 to 5 mm of the condylar head. Recently, proportional condylectomy, using point-of-care manufacturing 3-dimensional-cutting guides and intraoperative computed tomography control, has shown promising results, potentially eliminating the need for orthognathic surgery. This technique was successfully applied in a case involving a 29-year-old woman, resulting in normalized occlusion and aesthetics after subsequent orthodontic treatment, with stable outcomes 1-year post-treatment.
An experimental and computational investigation of the cyclopentene-containing peptide-derived compounds: focus on pseudo-cyclic motifs via intramolecular interactions
Authors: Bojarska Joanna , Breza Martin , Borowiecki Paweł , Madura Izabela D. , Kaczmarek Krzysztof , Ziora Zyta M. , Wolf Wojciech M.
Published: October 2024

Conformational flexibility is one of the main disadvantages of peptide-based compounds. We focus on their molecular ‘chameleonicity’ related to forming pseudo-cyclic motifs via modulation of weak intramolecular interactions. It is an appealing strategy for controlling equilibrium between the polar open and the nonpolar closed conformations. Within this context, we report here the crystal structure of the (
R
)-(2-
tert
-butoxycarbonyl)amino-1-oxo-3-phenyl)propyl)-1-cyclopentene (
1
), synthesis of which in high yield was achieved by a facile multi-step protocol. Our Cambridge Structural Database (CSD) overview for the peptide-based crystals revealed the exclusivity of this compound from the viewpoint of the unusual pseudo-bicyclic system via C–H
…
O and C–O
…
π interactions, in which cyclopentene shields the amide bond. Notably, cyclopentene as a bioisostere of proline is an appealing scaffold in medicinal chemistry. An extensive combined experimental and computational study provided more profound insight into the supramolecular landscape of
1
with respect to similar derivatives deposited in the CSD, including the tendency of cyclopentene for the generation of pseudo-cyclic motifs through weak H-bonding and π-based intramolecular interactions. These weak interactions have been examined by either the quantum theory of ‘atoms-in-molecules’ (QTAIM) or complex Hirshfeld surface methodology, including enrichment ratios, molecular electrostatic potential surfaces and energy frameworks. In all analysed crystals, all types of H-bonded motifs involving cyclopentene are formed at all levels of supramolecular architecture. A library of cyclopentene-based H-bonding synthons is provided. A molecular docking study depicted vital interactions of cyclopentene with key amino acid residues inside the active sites of two prominent protein kinases, uncovering the therapeutic potential of
1
against breast cancer. To a large extent, dispersion forces have significance in stabilizing the supramolecular structure of both ligand and bio-complex ligand–protein. Finally, the satisfactory
in silico
bio-pharmacokinetic profile of
1
related to drug-likeness and blood–brain barrier permeation was also revealed.
Lower gastrointestinal tract dysbiosis in persistent critical illness: a systematic review
Authors: Tang Emily , Doan Nicholas , Evans Tess , Litton Edward
Published: October 2024

Graphical abstract
Estimation of Rotavirus Vaccine Effectiveness Based on Whole Genome Sequences
Authors: Kwon Jiye , Jaimes Jose , Wikswo Mary E. , Klein Eileen J. , Staat Mary Allen , Chappell James D. , Weinberg Geoffrey A. , Harrison Christopher J , Selvarangan Rangaraj , Johnson Coreen , Weinberger Daniel M. , Warren Joshua L. , Esona Mathew D. , Bowen Michael D. , Pitzer Virginia E.
Published: October 2024

Introduction

Rotavirus vaccine evaluations have noted small differences in vaccine effectiveness (VE) against rotavirus genotypes, defined by the two outer capsid proteins (VP7 or G-type and VP4 or P-type). However, the genomic landscape of group A rotavirus (RVA) and the impact of the remaining nine genome segments (i.e., the “backbone”) on VE are not fully understood. We incorporated whole genome sequence (WGS) data to characterize viruses responsible for rotavirus-associated gastroenteritis (RVGE) between vaccinated and unvaccinated individuals in the United States (U.S.).

Methods

We analyzed 254 RVGE cases with WGS data from seven U.S. New Vaccine Surveillance Network sites during 2012-2016. Using a “sieve analysis” framework, we evaluated the variability in vaccine protection based on genetic distance (GD) defined at WGS-level as the percent nucleotide difference between each case strain and the vaccine strain(s). Strain-specific VE estimates were calculated using the test-negative design, controlling for potential cofounders. Separate analyses were performed for the monovalent Rotarix® vaccine (RV1, GlaxoSmithKline) and the pentavalent RotaTeq® vaccine (RV5, Merck & Co.). We also examined the site-specific genetic diversity of circulating RVA strains in relation to vaccine coverage.

Results

RV1-vaccinated cases were more likely to be infected with strains with greater than 9.6% GD from the RV1 vaccine strain (unadjusted OR = 3.03, 95% confidence interval (CI): 1.15, 8.03). Strains with a genogroup 1 (Wa-like) backbone represented the majority (99%) of cases below the threshold, whereas more distant strains had genetic backbones that resembled the genogroup 2 (DS-1-like) and reassortant strains. The RV1 vaccine showed evidence of substantially better protection against strains with lower GD to the RV1 strain (VE = 80%, 95% CI: 68%, 89%) compared to more distant strains (VE = 51%, 95% CI: = -29%, 82%). RV5 demonstrated a similar but less pronounced pattern of better protection against strains with a lower minimum GD to the vaccine strains. Sites with higher RV1 usage showed a shift in strain distribution towards greater GD from the RV1 strain, with a similar trend observed for RV5.

Conclusion

Incorporating the complete genomic structure of RVA reveals that vaccine protection correlates with the diversity of non-outer capsid proteins. Our WGS-based analysis more clearly differentiated vaccine protection than analyses based on VP7 and VP4 alone. With more RVA vaccines in the pipeline, understanding the contribution of all gene segments to immune protection will be key to ensuring the long-term success of RVA vaccination programs.
Subtelomere-specific condensed chromatin is regulated by three different histone modifications
Authors: Osaki Miho , Nurani Atika , Asano Nanoka , Otsubo Yoko , Kanoh Junko
Published: October 2024

In fission yeast, telomere-adjacent subtelomeres form a subtelomere-specific condensed chromatin structure, referred to as a knob, requiring histone H2A-S121 phosphorylation-dependent localization of Sgo2 at subtelomeres during interphase. However, the mechanism underlying specific Sgo2 localization in subtelomeres remains unclear. Our genetic screen identified Nts1, a histone deacetylase complex component, as a regulator of Sgo2 localization. Nts1 localized to subtelomeres during interphase and influenced histone H4 acetylation. The deletion of both Nts1 and Set2, a histone H3-K36 methyltransferase, led to the loss of Sgo2 at subtelomeres. These findings indicate that H4 deacetylation and H3-K36 methylation redundantly determine Sgo2 localization under H2A-S121 phosphorylation.
Interspecies hybridization as a route of accessory chromosome origin in fungal species infecting wild grasses
Authors: Fagundes Wagner C. , Möller Mareike , Feurtey Alice , Hansen Rune , Haueisen Janine , Salimi Fatemeh , Alizadeh Alireza , Stukenbrock Eva H.
Published: October 2024

Many fungal plant pathogens have dynamic genomic architectures that can contribute to rapid evolution and adaptation to new niches.Zymoseptoria tritici, an important fungal pathogen of wheat, has a compartmentalized and rapidly evolving genome. In the genome of the reference isolateZ. triticiIPO323, 8 of the 21 chromosomes are accessory. In spite of the profound impact on genome organization, the origin of accessory chromosomes inZ. triticiis still poorly understood. Combining genomics, transcriptomics and epigenomics, we discovered a new chromosome inZ. triticiisolates infecting wild grasses from the genusAegilops, and we use this discovery to study the origin of accessory chromosomes. The newly identified chromosome presents similar characteristics to known accessory chromosomes inZymoseptoriaspecies, including presence-absence variation, low gene expressionin vitroandin planta, and enrichment with heterochromatin-associated histone methylation marks (H3K27me3). Interestingly, we found an orthologous chromosome inZymoseptoria ardabiliae, a closely related fungal species also infecting wild grasses. This ortholog chromosome also presents accessory chromosomes characteristics, but lacks the enrichment of heterochromatin-associated methylation marks. Transcriptomic analyses revealed that the orthologous chromosome inZ. ardabiliaeharbors active transposable elements (TEs) congruent with lower signatures of host-genome defense mechanisms against TE expansion and spread (quantified as repeat-induced-point (RIP) mutation signatures). Our findings suggest that the chromosome has been exchanged betweenZ. triticiandZ. ardabiliaeby introgressive hybridization events underlining the relevance of hybridization in the evolution of new accessory chromosomes. We speculate that the regulation of TEs has not yet occurred on this new accessory chromosome inZ. ardabiliae, contributing to its rapid evolution.
Deep learning-based image classification reveals heterogeneous execution of cell death fates during viral infection
Authors: Centofanti Edoardo , Oyler-Yaniv Alon , Oyler-Yaniv Jennifer
Published: October 2024

Cell fate decisions, such as proliferation, differentiation, and death, are driven by complex molecular interactions and signaling cascades. While significant progress has been made in understanding the molecular determinants of these processes, historically, cell fate transitions were identified through light microscopy that focused on changes in cell morphology and function. Modern techniques have shifted towards probing molecular effectors to quantify these transitions, offering more precise quantification and mechanistic understanding. However, challenges remain in cases where the molecular signals are ambiguous, complicating the assignment of cell fate. During viral infection, programmed cell death (PCD) pathways, including apoptosis, necroptosis, and pyroptosis, exhibit complex signaling and molecular crosstalk. This can lead to simultaneous activation of multiple PCD pathways, which confounds assignment of cell fate based on molecular information alone. To address this challenge, we employed deep learning-based image classification of dying cells to analyze PCD in single Herpes Simplex Virus-1 (HSV-1)-infected cells. Our approach reveals that despite heterogeneous activation of signaling, individual cells adopt predominantly prototypical death morphologies. Nevertheless, PCD is executed heterogeneously within a uniform population of virus-infected cells and varies over time. These findings demonstrate that image-based phenotyping can provide valuable insights into cell fate decisions, complementing molecular assays.
Temporal multi-modal single-cell analyses reveal dynamic interactions of CAR-T cells with glioblastoma and targeting of antigen-negative neoplastic cells
Authors: Zhang Daniel Y. , Wang Xin , Sun Yusha , Cui Qi , Nelson Ernest , Zhang Zhijian , Huang Brian , Giles Josephine , Thokala Radhika , Connolly Daniel R. , Jacob Fadi , Wherry E John , Lucas Timothy , Chen H. Isaac , Shi Yanhong , Brem Steven , Binder Zev A. , Nasrallah MacLean P. , Salinas Ryan D. , O’Rourke Donald M. , Ming Guo-li , Song Hongjun
Published: October 2024

CAR-T therapy is a promising new immunotherapy for cancers, but its efficacy for solid tumors requires improvement. A detailed understanding of the interplay between solid tumors and CAR-T cells is critical. Here we report temporal, multi-modal, single-cell profiling of patient-derived glioblastoma organoids with CAR-T treatment. We found that all tumor cell types responded to CAR-T cell activation and contributed to an initially anti-tumor, but subsequently pro-tumor and immune-inhibitory microenvironment, accompanied by CAR-T cell exhaustion. Unexpectedly, CAR-T treatment attenuated glioma stem-like states of both antigen-positive and antigen-negative neoplastic cells and reduced their proliferation via diffusible factors, including IFNγ. Analysis of samples from additional patients, including those in clinical trials, supported these findings. Our study reveals the dynamic interplay among different tumor cells and T cells in adaptive responses to immunotherapy and identifies previously unappreciated benefits of CAR-T therapy directly on antigen-negative neoplastic cells that may be leveraged to enhance therapeutic efficacy.
Unique cuticular morphology of a truly marine insect,Echinophthirius horridusvon Olfers, 1816 (Phthiraptera: Echinophthiriidae)
Authors: White Tucker , Mikó István
Published: October 2024

Echinophthiriidae is a family of aquatic lice parasitizing aquatic carnivorans, each member distinguished by their uniquely modified, curved setae.Echinophthirius horridusis known to parasitize a wide range of phocid (earless) seals as opposed to exhibiting the more species-specific parasitism of other echinophthiriid lice. In this study, we use a combination of bright field microscopy, confocal laser scanning microscopy (CLSM), and line drawings to provide a detailed description of the general body setae ofE. horridusand discuss its possible significance as an adaptation to a marine lifestyle.
Stochastic Gene Expression in Auxin Signaling in the Floral Meristem ofArabidopsis thaliana
Authors: Kong Shuyao , Zhu Mingyuan , Roeder Adrienne H.K.
Published: October 2024

Cells display striking stochasticity in gene expression, which plays an important role in development, disease, and regeneration. Previous studies have found stochastic gene expression in bacteria, yeast, and from constitutive promoters in Arabidopsis. However, most promoters are non-constitutive. Stochastic gene expression from non-constitutive promoters in a multicellular organism, especially those with key developmental roles, remains largely uncharacterized. Here, we report stochastic expression of auxin responsive genes in the Arabidopsis floral meristem, using promoter reporters of DR5,ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN6(AHP6), andDNA BINDING WITH ONE FINGER5.8(DOF5.8). We found highly variable DR5 expression patterns among younger meristems. Such variability is not attributed to heterogeneity in auxin perception, but to downstream stochastic expression of DR5, mainly influenced by cell-intrinsic molecular noise. Expression ofAHP6andDOF5.8is also noisy, although their noise is lower and has distinct spatiotemporal patterns unlike DR5. Finally, we propose spatial averaging as a mechanism that buffers cellular gene expression noise, allowing the formation of robust global expression patterns. Our study reveals stochastic gene expression downstream of auxin signaling, a key developmental player. Thus, stochastic gene expression from non-constitutive promoters, including those involved in hormone signaling, is an ordinary part of multicellular life.
Evolution of g-Type Lysozymes in Metazoa: Insights into Immunity and Digestive Adaptations
Authors: Mukherjee Krishanu , Moroz Leonid L.
Published: October 2024

Exploring the evolutionary dynamics of lysozymes is critical for advancing our knowledge of adaptations in immune and digestive systems. Here, we characterize the distribution of a unique class of lysozymes known as g-type, which hydrolyze key components of bacterial cell walls. Notably, many basal metazoan groups, including ctenophores, sponges, and choanoflagellates (the sister group of Metazoa), lack g-type lysozymes. We reveal a mosaic distribution of these genes, particularly within lophotrochozoans/spiralians, suggesting the lateral gene transfer (LGT) events from predatory myxobacteria played a role in their acquisition, enabling specialized dietary and defensive adaptations. We further identify two major groups of g-type lysozymes based on their widespread distribution in gastropods. Despite their sequence diversity, these lysozymes maintain conserved structural integrity that is crucial for enzymatic activity, underscoring independent evolutionary pathways where g-type lysozymes have developed functionalities typically associated with different lysozyme types in other species. Specifically, usingAplysia californicaas a reference species, we identified three distinct g-type lysozyme genes: two are expressed in organs linked to both feeding and defense, and the third exhibits broader distribution, likely associated with immune functions. These findings advance our understanding of the evolutionary dynamics shaping the recruitment and mosaic functional diversification of these enzymes across metazoans, offering new insights into ecological physiology and physiological evolution as emerging fields.
Phylogeny-aware simulations suggest a low impact of unsampled lineages in the inference of gene flow during eukaryogenesis
Authors: Bernabeu Moisès , Manzano-Morales Saioa , Gabaldón Toni
Published: October 2024

Gene phylogenies are broadly used to analyse events of horizontal gene transfer, namely, their presence, the potential donor and acceptor lineages, and their relative timing. Recent phylogenomics analyses have reconstructed a relative chronology of gene acquisitions in the lineage leading to the eukaryotes, revealing waves of acquisition from different donors before and after the mitochondrial endosymbiosis. However, a recognised caveat is the potential biases introduced by the presence of incomplete taxon sampling resulting in so-called “ghost” lineages. Here, we assessed the robustness of the gene phylogeny-based branch length ratio method in the inference of the relative ordering of gene acquisition events during eukaryogenesis. We introduce a novel simulation framework that populates a known dated Tree of Life with plausible “ghost” lineages and simulates their gene transfers to the lineage leading to the last eukaryotic common ancestor. Our simulations suggest a generally low probability of misinterpreting the relative order of gene acquisitions from distinct ghost donors. However, we identify specific problematic phylogenetic placements where unsampled lineages are more likely to produce misleading results. Overall, our approach offers valuable guidance for the interpretation of future work on eukaryogenesis, and can be readily adapted to other evolutionary scenarios.
Single-Cell Data Integration and Cell Type Annotation through Contrastive Adversarial Open-set Domain Adaptation
Authors: Aminzadeh Fatemeh , Wu Jun , He Jingrui , Saberi Morteza , Vafaee Fatemeh
Published: October 2024

Single-cell sequencing technologies have enabled in-depth analysis of cellular heterogeneity across tissues and disease contexts. However, as datasets increase in size and complexity, characterizing diverse cellular populations, integrating data across multiple modalities, and correcting batch effects remain challenges. We present SAFAARI (Single-cell Annotation and Fusion with Adversarial Open-Set Domain Adaptation Reliable for Data Integration), a unified deep learning framework designed for cell annotation, batch correction, and multi-omics integration. SAFAARI leverages supervised contrastive learning and adversarial domain adaptation to achieve domain-invariant embeddings and enables label transfer across datasets, addressing challenges posed by batch effects, biological domain shifts, and multi-omics modalities. SAFAARI identifies novel cell types and mitigates class imbalance to enhance the detection of rare cell types. Through comprehensive benchmarking, we evaluated SAFAARI against existing annotation and integration methods across real-world datasets exhibiting batch effects and domain shifts, as well as simulated and multi-omics data. SAFAARI demonstrated scalability and robust performance in cell annotation via label transfer across heterogeneous datasets, detection of unknown cell types, correction of batch effects, and cross-omics data integration while leveraging available annotations for improved integration. SAFAARI’s innovative approach outperformed competing methods in both qualitative and quantitative metrics, offering a flexible, accurate, and scalable solution for single-cell analysis with broad applicability to diverse biological and clinical research questions.
Patterns of extreme outlier RNA expression in population data reveal sporadic over-activation of genes with co-regulated modules in subsets of individuals
Authors: Xie Chen , Künzel Sven , Zhang Wenyu , Hathaway Cassandra A. , Tworoger Shelley S. , Tautz Diethard
Published: October 2024

Background

Most RNA-Seq datasets harbor genes with extreme expression levels in some samples. Such extreme outliers are usually treated as technical errors and are removed from the data before further statistical analysis. Here we focus on the patterns of such outlier expression.

Results

Our study is based on multiple datasets, including outbred and inbred mice, humans from the GTEx dataset, differentDrosophilaspecies and single-nuclei sequencing experiments from human brain tissues. All show comparable general patterns of outlier expression. Different individuals can harbor very different numbers of outliers, with some individuals showing extreme numbers in only one out of several organs of the respective individual. A three-generation family analysis in mice was generated and analyzed for the inheritance of outlier patterns. We find that most extreme over-expressions are not inherited, i.e., appear to be sporadically generated in individuals. Still, co-regulated outlier expressions are identifiable in various gene groups, and some correspond with known pathways. Among the co-regulated genes with extreme outlier expression are also the hormone genes prolactin and growth hormone, both in mice and humans, for which we include also protein level data from human cohorts.

Conclusions

We show that outlier patterns of gene expression are a biological reality occurring universally across tissues and species. Most of the outlier expressions are spontaneous and not inherited. We discuss the possibility that the outlier patterns reflect edge of chaos effects that are expected for systems of non-linear interactions and feedback loops, such as gene regulatory networks.
FT-like genes in Cannabis and hops: sex specific expression and copy-number variation may explain flowering time variation
Authors: Dowling Caroline A. , Michael Todd P. , McCabe Paul F. , Schilling Susanne , Melzer Rainer
Published: October 2024

Cannabis sativais a fascinating, yet under-researched, species. To facilitate the global expansion ofC. sativacultivation a greater understanding of flowering time control is crucial. ThePEBPgene family consists of universal promoters and repressors of flowering, with homologs ofFLOWERING LOCUS T(FT) being highly conserved key regulators of flowering.FTencodes florigen, and balancing the florigen and anti-florigen signals is key for fine-tuning a crop’s flowering to local climatic conditions. Here, we provide an in-depth characterisation of thePEBPgene family inC. sativaand the closely related speciesH. lupulus.Phylogenetic analysis reveals expansion ofFTandTFL1/CENclades in the Cannabaceae. The retention of the duplicatedPEBPgenes likely has functional significance with divergent sequences and expression patterns hinting at signatures of sub-functionalisation. We speculate that duplicatedPEBPgenes have been crucial to the evolution of photoperiod insensitivity and sexually dimorphic flowering inC. sativaand harnessing the available genetic variation for these traits will be key for establishing this future crop.
The FIP 1.0 Data Set: Highly Resolved Annotated Image Time Series of 4,000 Wheat Plots Grown in Six Years
Authors: Roth Lukas , Boss Mike , Kirchgessner Norbert , Aasen Helge , Aguirre-Cuellar Brenda Patricia , Akiina Price Pius Atuah , Anderegg Jonas , Gajardo Castillo Joaquin , Chen Xiaoran , Corrado Simon , Cybulski Krzysztof , Keller Beat , Kortstee Stefan Göbel , Kronenberg Lukas , Liebisch Frank , Nousi Paraskevi , Oppliger Corina , Perich Gregor , Pfeifer Johannes , Yu Kang , Storni Nicola , Tschurr Flavian , Treier Simon , Volpi Michele , Zellweger Hansueli , Zumsteg Olivia , Hund Andreas , Walter Achim
Published: October 2024

Background

Understanding genotype-environment interactions of plants is crucial for crop improvement, yet limited by the scarcity of quality phenotyping data. This data note presents the Field Phenotyping Platform 1.0 data set, a comprehensive resource for winter wheat research that combines imaging, trait, environmental, and genetic data.

Findings

We provide time series data for more than 4,000 wheat plots, including aligned high-resolution image sequences totaling more than 151,000 aligned images across six years. Measurement data for eight key wheat traits is included, namely canopy cover values, plant heights, wheat head counts, senescence ratings, heading date, final plant height, grain yield, and protein content. Genetic marker information and environmental data complement the time series. Data quality is demonstrated through heritability analyses and genomic prediction models, achieving accuracies aligned with previous research.

Conclusions

This extensive data set offers opportunities for advancing crop modeling and phenotyping techniques, enabling researchers to develop novel approaches for understanding genotype-environment interactions, analyzing growth dynamics, and predicting crop performance. By making this resource publicly available, we aim to accelerate research in climate-adaptive agriculture and foster collaboration between plant science and computer vision communities.
D-lactate derived from intestinal bacteria drives lysine D-lactylation to modulate transcription in liver cells
Authors: Zang Yong , Zhang Jianji , Xia Mingxin , Wang Aiyuan , Fan Zilong , Han Yanpu , Zhang Hui , Wang Siyu , Niu Ziping , Wu Jingya , Bai Xue , Tian Shanshan , Chen Chen , Zhai Guijin , Dong Hanyang , Hu Deqing , Cheng Zhongyi , Zhang Kai
Published: October 2024

Emerging evidence indicates that the accumulated D-lactate (D-la) from intestinal bacteria induces diverse effects in human intestinal injury diseases. However, its regulatory mechanism and functional consequence remain unclear. Here, we show that the secreted D-la induces lysine D-lactylation (K-Dla) to modulate transcription in host cells. We uncover K-Dla in HepG2 cells stimulated by D-la fromE. colisecretions. Then, we confirm the occurrence of D-la-driven K-Dla by four orthogonal approaches. We further validate that the existence of K-Dla in organisms by detecting the mouse liver and human intestinal tissue. Besides, we demonstrate a SCOT1-catalyzed biosynthetic pathway of D-lactyl-CoA, serving as a key donor for K-Dla. Next, we identify the K-Dla landscape with 2895 sites and further suggest the regulation of histone K-Dla in transcription by MNase ChIP-seq and RNA-seq assays. Finally, we show the potential effect of K-Dla on inhibiting the hepatocellular carcinoma cell proliferation. In summary, we report that the secreted D-la can induce K-Dla to regulate transcription, providing a new insight into the function of D-la secreted by gut microbiota and the effect of protein chemical modifications induced by bacterial secretions.
Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer factor-mediated zygotic genome activation
Authors: Marsh Audrey J. , Pirogov Sergei , Ruffridge Abby J. , Sajwan Suresh , Gibson Tyler J. , Hunt George , Kaur Yadwinder , Harrison Melissa M. , Mannervik Mattias
Published: October 2024

Immediately after fertilization the genome is transcriptionally quiescent. Maternally encoded pioneer transcription factors reprogram the chromatin state and facilitate the transcription of the zygotic genome. InDrosophila, transcription is initiated by the pioneer factor Zelda. While Zelda-occupied sites are enriched with histone acetylation, a post-translational mark associated with activecis-regulatory regions, the functional relationship between Zelda and histone acetylation in zygotic genome activation remained unclear. We show that Zelda-mediated recruitment of the histone acetyltransferase CBP is essential for zygotic transcription. CBP catalytic activity is necessary for release of RNA Polymerase II (Pol II) into transcription elongation and for embryonic development. However, CBP also activates zygotic transcription independent of acetylation through Pol II recruitment. Neither acetylation nor CBP are required for the pioneering function of Zelda. Our data suggest that pioneer factor-mediated recruitment of CBP is a conserved mechanism required to activate zygotic transcription but that this role is separable from the function of pioneer factors in restructuring chromatin accessibility.
Trans-generational adaptation to maternal climate through hormone transport in plants
Authors: Chen Xiaochao , Bezodis William , González-Suárez Pablo , Knitlhoffer Vanda , Goldson Andrew , Lister Ashleigh , Macaulay Iain , Penfield Steven
Published: October 2024

Whether organisms can inherit parental adaptations to the environment is a major question in evolutionary biology. Plant development is highly plastic and dependent on the seasonal cues which are used to control growth and reproduction. Seed dormancy and germination are key traits which respond strongly to temperature during seed development and here we show that progeny adaptation to seasonal climate is inherited from the mother plant. Loss of maternal LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) causes an inability of progeny seeds to sense temperature and this is linked mechanistically to reduced ABA levels in seeds and activation of the primary nitrate response. At the single cell level, small changes in temperature activate nitrate signalling specifically in the mother, and ABA biosensor imaging reveals temperature-dependent fluxes of ABA into seeds necessary for dormancy induction. Thus, we reveal that progeny seeds inherit the climate adaptation of mother plants via active hormone transport during seed set.
Exploring the Potential of Malvidin and Echiodinin as Probable Antileishmanial Agents ThroughIn SilicoAnalysis AndIn VitroEfficacy
Authors: Goyzueta-Mamani Luis Daniel , Pagliara Lage Daniela , Barazorda-Ccahuana Haruna Luz , Paco-Chipana Margot , Candia-Puma Mayron Antonio , Davila-Del-Carpio Gonzalo , Sobreira Galdino Alexsandro , Machado-de-Avila Ricardo Andrez , Cordeiro Giunchetti Rodolfo , D’Antonio Edward L. , Ferraz Coelho Eduardo Antonio , Chávez-Fumagalli Miguel Angel
Published: October 2024

Leishmaniasis is a neglected tropical disease, caused by distinctLeishmaniaspecies, which have significant public health challenges due to treatment limitations such as toxicity, high cost, and drug resistance. This study explores thein vitropotential of Malvidin and Echioidinin as probable antileishmanial agents againstLeishmania amazonensis,L. braziliensis, andL. infantum, comparing their efficacy to Amphotericin B (AmpB), a standard drug. Malvidin was more potent than Echioidinin across all parasite stages and species. ForL. amazonensis, Malvidin’s inhibitory concentration (IC50) values were 197.71±17.20 µM and 258.07±17 µM (stationary and axenic amastigotes, respectively); whereas Echioidinin revealed IC50values of 272.99±29.90 μM and 335.96±19.35 μM (stationary and axenic amastigotes, respectively). AmpB showed IC50values of 0.06±0.01 µM and 0.10±0.03 µM, respectively. Malvidin demonstrated lower cytotoxicity activity in mammalian cells with a cytotoxic concentration (CC50) value of 2,920.31±80.29 µM, while AmpB’s showed a value of 1.06±0.12 µM. Malvidin also exhibited favorable selectivity index (SI) values. Malvidin reduced infection rates by up to 35.75% inL. amazonensis-infected macrophages.In silicoanalysis uncovered strong binding interactions between Malvidin and enzyme arginase in the three species, with key residues such as HIS139 and PRO258 playing a crucial role. Tissue-specific markers expression analysis highlighted the potential Malvidin’s modulation of genes involved in oxidative stress and DNA repair, including glyoxalase 1 (GLO1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1). Thein vitroandin silicodata corroborate the hypothesis that Malvidin is safe and can control theLeishmaniaparasites as a new natural compound for treatment. To further assess its therapeutic potential,in vivostudies are required to evaluate Malvidin’s efficacy, safety, and pharmacokinetics in animal models, which will be essential for validating its role as a candidate for leishmaniasis treatment.
Suspended Tissue Open Microfluidic Patterning (STOMP)
Authors: Haack Amanda J. , Brown Lauren G. , Goldstein Alex J. , Mulimani Priti , Berthier Jean , Viswanathan Asha R. , Kopyeva Irina , Whitten Jamison M. , Lin Ariel , Nguyen Serena H. , Leahy Thomas P. , Bouker Ella E. , Padgett Ruby M. , Mazzawi Natalie A. , Tokihiro Jodie C. , Bretherton Ross C. , Wu Aaliyah , Tapscott Stephen J. , DeForest Cole A. , Popowics Tracy E. , Berthier Erwin , Sniadecki Nathan J. , Theberge Ashleigh B.
Published: October 2024

Cell-laden hydrogel constructs suspended between pillars are powerful tools for modeling tissue structure and physiology, though current fabrication techniques often limit them to uniform compositions. In contrast, tissues are complex in nature with spatial arrangements of cell types and extracellular matrices. Thus, we present Suspended Tissue Open Microfluidic Patterning (STOMP), which utilizes a removable, open microfluidic patterning channel to pattern multiple spatial regions across a single suspended tissue. The STOMP platform contains capillary pinning features along the open channel that controls the fluid front, allowing multiple cell and extracellular matrix precursors to be pipetted into one tissue. We have used this technique to pattern suspended tissues with multiple regional components using a variety of native and synthetic extracellular matrices, including fibrin, collagen, and poly(ethylene glycol). Here, we demonstrate that STOMP models a region of fibrosis in a functional heart tissue and a bone-ligament junction in periodontal tissues. Additionally, the STOMP platform can be customized to allow patterning of suspended cores and more spatial configurations, enhancing its utility in complex tissue modeling. STOMP is a versatile technique for generating suspended tissue models with increased control over cell and hydrogel composition to model interfacial tissue regions in a suspended tissue.