bluuebunny/crossref_metadata_2025 huggingface dataset:
Fully automatic summarization of radiology reports using natural language processing with language models
Authors: Nishio Mizuho , Matsunaga Takaaki , Matsuo Hidetoshi , Nogami Munenobu , Kurata Yasuhisa , Fujimoto Koji , Sugiyama Osamu , Akashi Toshiaki , Aoki Shigeki , Murakami Takamichi
Published: December 2023

Natural language processing using language models has yielded promising results in various fields. The use of language models may help improve the workflow of radiologists. This retrospective study aimed to construct and evaluate language models for the automatic summarization of radiology reports. Two datasets of radiology reports were used: MIMIC-CXR and the Japan Medical Image Database (JMID). MIMIC-CXR is an open dataset comprising chest radiograph reports. JMID is a large dataset of CT and MRI reports comprising reports from 10 academic medical centers in Japan. A total of 128,032 and 1,101,271 reports from the MIMIC-CXR and JMID, respectively, were included in this study. Four Text-to-Text Transfer Transformer (T5) models were constructed. Recall-Oriented Understudy for Gisting Evaluation (ROUGE), a quantitative metric, was used to evaluate the quality of text summarized from 19,205 and 58,043 test sets from MIMIC-CXR and JMID, respectively. The Wilcoxon signed-rank test was utilized to evaluate the differences among the ROUGE values of the four T5 models. In addition, subsets of automatically summarized text in the test sets were manually evaluated by two radiologists. Based on the Wilcoxon signed-rank test, the best T5 models were selected for the automatic summarization. The quantitative metrics of the best T5 models were as follows: ROUGE-1 = 57.75 ± 30.99, ROUGE-2 = 49.96 ± 35.36, and ROUGE-L = 54.07 ± 32.48 in MIMIC-CXR; ROUGE-1 = 50.00 ± 29.24, ROUGE-2 = 39.66 ± 30.21, and ROUGE-L = 47.87 ± 29.44 in JMID. The radiologists’ evaluations revealed that 86% (86/100) and 85% (85/100) of the texts automatically summarized from MIMIC-CXR and JMID, respectively, were clinically useful. The T5 models constructed in this study were capable of automatic summarization of radiology reports. The radiologists’ evaluations revealed that most of the automatically summarized texts were clinically valuable.
Acute intermittent hypoxia in people living with chronic stroke – a preliminary study to examine safety and efficacy as a neurorehabilitation intervention
Authors: Pearcey Gregory EP , Barry Alexander J , Sandhu Milap S , Carroll Timothy , Roth Elliot J , Rymer W Zev
Published: December 2023

Background and Purpose

Acute intermittent hypoxia (AIH) is a novel therapeutic intervention that has the potential to facilitate recovery of function, but its safety and efficacy have not been tested in people with stroke. The purpose here was to examine whether AIH is safe and effective in people with stroke.

Methods

Participants (n=10) with a unilateral, ischemic, hemispheric stroke were assessed before and following 4 sessions of AIH. Clinical tests and upper limb strength were assessed before, ∼15-30 minutes, and ∼60 minutes after the intervention.

Results

AIH was well-tolerated and there were no adverse events observed. Although no changes in strength were detected for the less-affected limb, grip strength and elbow flexion force of the more-affected limb was increased after AIH.

Conclusions

AIH appears to be potentially safe and effective for improving strength in the more-affected limb in people with stroke. Future work should explore the use of AIH to enhance task-specific training-induced plasticity.
Connecting the Dots: Systematic Exploration of COVID-19 and Acute Kidney Injury through Meta-Analysis
Authors: Sarker Md. Safiullah , Jahan Rubiyat
Published: December 2023

Objective

COVID-19 pandemic is a danger for the whole world. Also, our knowledge about acute kidney injury (AKI) in COVID-19 patients is incomplete. Few studies informed that the problem of AKI is a common complication, but other studies concluded that AKI is only an unusual event during COVID-19 infection. This study using meta-analysis tools aimed to find disease progression and mortality risk in affected population.

Methods

We systematically reviewed the literature on COVID-19 and its association with AKI as per PRISMA guideline. All authors independently performed a literature search until 8th June 2023. We included studies which reported clinical characteristics, incidence of AKI, and the death risk with AKI during COVID-19 infection.

Findings

We have included five studies and all of them reported older age (73-75) and males (67-84.2%) were risk factors for patient illness. COVID-19 patients with AKI had more than five times mortality risk of those without AKI. Diagnosis time after disease onset was 8.5 days (IQR, [4–11]). Fatality time after initial hospital admission was 13.5 days (IQR, 8–17). In non-survivors, systemic inflammation with high temperature, abnormal respiratory rate, acute myocardial injury, and acute respiratory distress syndrome (ARDS) were observed. Abnormal biochemical analytes and immunological markers were observed.

Conclusion

Our analyses indicate that patients experienced repeated changes in biochemical analytes and immune marker with the progression of the disease. It indicates the requirement of early management and treatment. Further study is required to conclude and to have better knowledge of AKI mechanism with COVID-19 infection.
A female-biased gene expression signature of dominance in cooperatively breeding meerkats
Authors: Ryan Campbell C. , Manser Marta , Shiratori Mari , Williams Kelly , Barreiro Luis , Clutton-Brock Tim , Tung Jenny
Published: December 2023

Dominance is a primary determinant of social dynamics and resource access in social animals. Recent studies show that dominance is also reflected in the gene regulatory profiles of peripheral immune cells. However, the strength and direction of this relationship differs across the species and sex combinations investigated, potentially due to variation in the predictors and energetic consequences of dominant status. To test this possibility, we investigated the association between social status and gene expression in the blood of wild meerkats (Suricata suricatta; n=113 unique individuals), including in response to lipopolysaccharide, Gardiquimod, and glucocorticoid stimulation. Meerkats are cooperatively breeding social carnivores in which breeding females physically outcompete other females to suppress reproduction, resulting in high reproductive skew. They therefore present an opportunity to disentangle the effects of social dominance from those of sexper se. We identify a sex-specific signature of dominance, including 1,045 differentially expressed genes in females but none in males. Dominant females exhibit elevated activity in innate immune pathways and an exacerbated response to LPS challenge. In this respect, female meerkats resemble wild male baboons (for which similar data are available), where physical competition is also central to determining rank hierarchies and mating effort is high. However, they differ from female primates in which social status is nepotistically determined. Our results support the hypothesis that the gene regulatory signature of social status depends on the determinants and energetic costs of social dominance. They also support potential life history trade-offs between investment in reproduction versus somatic maintenance.
Semantical and Geometrical Protein Encoding Toward Enhanced Bioactivity and Thermostability
Authors: Tan Yang , Zhou Bingxin , Zheng Lirong , Fan Guisheng , Hong Liang
Published: December 2023

Protein engineering is a pivotal aspect of synthetic biology, involving the modification of amino acids within existing protein sequences to achieve novel or enhanced functionalities and physical properties. Accurate prediction of protein variant effects requires a thorough understanding of protein sequence, structure, and function. Deep learning methods have demonstrated remarkable performance in guiding protein modification for improved functionality. However, existing approaches predominantly rely on protein sequences, which face challenges in efficiently encoding the geometric aspects of amino acids’ local environment and often fall short in capturing crucial details related to protein folding stability, internal molecular interactions, and bio-functions. Furthermore, there lacks a fundamental evaluation for developed methods in predicting protein thermostability, although it is a key physical property that is frequently investigated in practice. To address these challenges, this paper introduces a novel pre-training framework that integrates sequential and geometric encoders for protein primary and tertiary structures. This framework guides mutation directions toward desired traits by simulating natural selection on wild-type proteins and evaluates variant effects based on their fitness to perform specific functions. We assess the proposed approach using three benchmarks comprising over 300 deep mutational scanning assays. The prediction results showcase exceptional performance across extensive experiments when compared to other zero-shot learning methods, all while maintaining a minimal cost in terms of trainable parameters. This study not only proposes an effective framework for more accurate and comprehensive predictions to facilitate efficient protein engineering, but also enhances thein silicoassessment system for future deep learning models to better align with empirical requirements. The PyTorch implementation are available athttps://github.com/tyang816/ProtSSN.
Conservation assessment of human splice site annotation based on a 470-genome alignment
Authors: Minkin Ilia , Salzberg Steven L.
Published: December 2023

Despite many improvements over the years, the annotation of the human genome remains imperfect. The use of evolutionarily conserved sequences provides a strategy for selecting a high-confidence subset of the annotation. Using the latest whole genome alignment, we found that splice sites from protein-coding genes in the high-quality MANE annotation are consistently conserved across more than 350 species. We also studied splice sites from the RefSeq, GENCODE, and CHESS databases not present in MANE. In addition, we analyzed the completeness of the alignment with respect to the human genome annotations and described a method that would allow us to fix up to 50of the protein-coding exons. We trained a logistic regression classifier to distinguish between the conservation exhibited by sites from MANE versus sites chosen randomly from neutrally evolving sequences. We found that splice sites classified by our model as well-supported have lower SNP rates and better transcriptomic support. We then computed a subset of transcripts using only “well-supported” splice sites or ones from MANE. This subset is enriched in high-confidence transcripts of the major gene catalogs that appear to be under purifying selection and are more likely to be correct and functionally relevant.

Graphical abstract
Adaptive stretching of representations across brain regions and deep learning model layers
Authors: Zhang Xin-Ya , Bobadilla-Suarez Sebastian , Luo Xiaoliang , Lemonari Marilena , Brincat Scott L. , Siegel Markus , Miller Earl K. , Love Bradley C.
Published: December 2023

Prefrontal cortex (PFC) is known to modulate the visual system to favor goal-relevant information by accentuating task-relevant stimulus dimensions. Does the brain broadly re-configures itself to optimize performance by stretching visual representations along task-relevant dimensions? We considered a task that required monkeys to selectively attend on a trial-by-trial basis to one of two dimensions (color or motion direction) to make a decision. Except for V4 (color bound) and MT (motion bound), the brain radically re-configured itself to stretch representations along task-relevant dimensions in lateral PFC, frontal eye fields (FEF), lateral intraparietal cortex (LIP), and inferotemporal cortex (IT). Spike timing was crucial to this code. A deep learning model was trained on the same visual input and rewards as the monkeys. Despite lacking an explicit selective attention or other control mechanism, the model displayed task-relevant stretching as a consequence of error minimization, indicating that stretching is an adaptive strategy.
Complex sporulation-specific expression of transcription termination factor Rho highlights its involvement inBacillus subtiliscell differentiation
Authors: Bidnenko Vladimir , Chastanet Arnaud , Péchoux Christine , Redko-Hamel Yulia , Pellegrini Olivier , Durand Sylvain , Condon Ciarán , Boudvillain Marc , Jules Matthieu , Bidnenko Elena
Published: December 2023

Transcription termination factor Rho controls pervasive, mainly antisense, transcription initiated at cryptic signals or resulting from read-through at weak terminators in various bacterial species. InBacillus subtilis, Rho is intricately involved in the regulation of phenomena associated with the adaptation to stationary phase and cell differentiation including the ultimate survival program of sporulation.

While knockout or overexpression of therhogene alters global transcription and modifies cell physiology, in wild-typeB. subtiliscells, the reduction of Rho levels during the transition to stationary phase is necessary for both initiation and implementation of the sporulation program. However, the mechanisms that govern Rho expression throughout the cell cycle remain largely unknown.

Here, we demonstrate that, besides the previously identified vegetative SigA-dependent promoter active during exponential growth, two distinct mechanisms ensure a spatiotemporal expression of therhogene during sporulation. In the mother cell of the sporangium,rhoexpression occurs through the read-through transcription initiated at the distal SigH-dependent and Spo0A∼P-regulated promoter of thespo0Fgene. In the forespore,rhois transcribed from a genuine promoter recognized by the alternative sigma factor SigF. These regulatory elements compensate for the inactivation of SigA-dependentrhoexpression at the end of exponential growth and allow the critical “refueling” of Rho protein in both compartments of the sporangium. We show that alteringrhoexpression in the mother cell or in the forespore affects differently the properties and the morphology of mature spores. Moreover, spores formed in the absence of Rho are impaired in their ability to revive under favorable growth conditions, exhibiting accelerated germination and slow outgrowth. Finally, we show that optimal outgrowth of the wild-type spores requires the expression ofrhoduring spore maturation and additionally after spore germination.
TheWinglessPlanar Cell Polarity pathway is essential for optimal activity-dependent synaptic plasticity
Authors: Dominicci-Cotto Carihann , Vazquez Mariam , Marie Bruno
Published: December 2023

From fly to man, the Wingless (Wg) / Wnt signaling molecule is essential for both the stability and plasticity of the nervous system. TheDrosophilaneuromuscular junction(NMJ) has proven to be a useful system for deciphering the role of Wg in directing activity-dependent synaptic plasticity, which, in the motoneuron, has been shown to be dependent on both the canonical and the noncanonical calcium Wg pathways. Here we show that the noncanonical planar cell polarity (PCP) pathway is an essential component of the Wg signaling system controlling plasticity at the motoneuron synapse. We present evidence that disturbing the PCP pathway leads to a perturbation in activity-dependent synaptic plasticity (ADSP). We first show that a PCP-specific allele ofdishevelled(dsh) affects thede novosynaptic structures produced during ADSP. We then show that the Rho GTPases downstream of Dsh in the PCP pathway are also involved in regulating the morphological changes that take place after repeated stimulation. Finally, we show that Jun kinase is essential for this phenomenon, whereas we found no indication of the involvement of the transcription factor complex AP1 (Jun/Fos). This work shows the involvement of the neuronal PCP signaling pathway in supporting ADSP. Because we find that AP1 mutants can perform ADSP adequately, we hypothesize that, upon Wg activation, the Rho GTPases and Jun kinase are involved locally at the synapse, in instructing cytoskeletal dynamics responsible for the appearance of the morphological changes occurring during ADSP.
FGF9, a potent mitogen, is a new ligand for integrin αvβ3, and the FGF9 mutant defective in integrin binding acts as an antagonist
Authors: Chang Chih-Chieh , Takada Yoko K , Cheng Chao-Wen , Maekawa Yukina , Mori Seiji , Takada Yoshikazu
Published: December 2023

FGF9 is a potent mitogen and survival factor, but FGF9 protein level is generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3 and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR, and suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here we show that docking simulation of interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We showed that FGF9 actually bound to integrin αvβ3, and generated an FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis induced by WT FGF9 and suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.
Role of Immature Choroid Plexus in the Pathology of Autism Spectrum Disorder
Authors: Tanabe Motoi , Saito Yuga , Takasaki Ayaka , Nakano Keita , Suzuki Chikako , Kawamura Nao , Hattori Aki , Nagashima Shun , Oikawa Mami , Yanagi Shigeru , Yamaguchi Tomoyuki , Fukuda Toshifumi
Published: December 2023

During gestation, the choroid plexus (ChP) produces protein-rich cerebrospinal fluid and matures prior to brain development. It is assumed that ChP dysfunction has a profound effect on developmental neuropsychiatric disorders, such as Autism Spectrum Disorder (ASD). However, the mechanisms linking immature ChP to the onset of ASD remain unclear. In this study, we found that ChP-specific CAMDI-knockout mice developed an immature ChP, alongside decreased multiciliogenesis and expression of differentiation marker genes following disruption of the cerebrospinal fluid barrier. These mice exhibited ASD-like behaviors, including impaired socialization with delayed critical period. Additionally, administration of Metformin, an FDA-approved drug, before the critical period achieved ChP maturation and restored social behaviors. Furthermore, ASD model mice and ASD patient-derived organoids developed immature ChP. These results indicate towards involvement of immature ChP in the pathogenesis of ASD and suggest the targeting of functional maturation of ChP as a therapeutic strategy for ASD.
Intracellular Ebola Virus nucleocapsid assembly revealed by in situ cryo-electron tomography.
Authors: Watanabe Reika , Zyla Dawid , Parekh Diptiben , Hong Connor , Jones Ying , Schendel Sharon L. , Wan Willian , Castillon Guillaume , Saphire Erica Ollmann
Published: December 2023

Filoviruses, including Ebola and Marburg viruses, cause hemorrhagic fevers with up to 90% lethality. The viral nucleocapsid is assembled by polymerization of the nucleoprotein (NP) along the viral genome, together with the viral proteins VP24 and VP35. We employed cryo-electron tomography of cells transfected with viral proteins and infected with model Ebola virus, to illuminate assembly intermediates as well as a 9 Å of the complete intracellular assembly. This structure reveals a previously unresolved, third, and outer layer of NP complexed with VP35. The intrinsically-disordered-region together with the C-terminal domain of this outer layer of NP provides the constant-width between intracellular nucleocapsid bundles and likely functions as a flexible tether to the viral matrix protein in virion. A comparison of intracellular nucleocapsid with prior in-virion nucleocapsid structures reveals the nucleocapsid further condenses vertically in-virion. The interfaces responsible for nucleocapsid assembly are highly conserved and offer targets for broadly effective antivirals.
Alternative ergosterol biosynthetic pathways confer antifungal drug resistance in the human pathogens within theMucorspecies complex
Authors: Navarro-Mendoza María Isabel , Pérez-Arques Carlos , Parker Josie , Xu Ziyan , Kelly Steven , Heitman Joseph
Published: December 2023

Mucormycoses are emerging fungal infections caused by a variety of heterogeneous species within the Mucorales order. Among theMucorspecies complex,Mucor circinelloidesis the most frequently isolated pathogen in mucormycosis patients and despite its clinical significance, there is an absence of established genome manipulation techniques to conduct molecular patho-genesis studies. In this study, we generated a spontaneous uracil auxotrophic strain and developed a genetic transformation procedure to analyze molecular mechanisms conferring antifungal drug resistance. With this new model, phenotypic analyses of gene deletion mutants were conducted to define Erg3 and Erg6a as key biosynthetic enzymes in theM. circinelloidesergosterol pathway. Erg3 is a C-5 sterol desaturase involved in growth, sporulation, virulence, and azole susceptibility. In other fungal pathogens,erg3mutations confer azole resistance because Erg3 catalyzes the production of a toxic diol upon azole exposure. Surprisingly,M. circinelloidesproduces only trace amounts of this toxic diol and yet, it is still susceptible to posaconazole and isavuconazole due to alterations in membrane sterol composition. These alterations are severely aggravated byerg3Δ mutations, resulting in ergosterol depletion and consequently, hy-persusceptibility to azoles. We also identified Erg6a as the main C-24 sterol methyltransferase, whose activity may be partially rescued by the paralogs Erg6b and Erg6c. Loss of Erg6a function diverts ergosterol synthesis to the production of cholesta-type sterols, resulting in resistance to amphotericin B. Our findings suggest that mutations or epimutations causing loss of Erg6 function may arise during human infections, resulting in antifungal drug resistance to first-line treatments against mucormycoses.

Importance

TheMucorspecies complex comprises a variety of opportunistic pathogens known to cause mucormycosis, a potentially lethal fungal infection with limited therapeutic options. The only effective first-line treatments against mucormycosis consist of liposomal formulations of amphotericin B and the triazoles posaconazole and isavuconazole, all of which target components within the ergosterol biosynthetic pathway. This study uncoveredM. circinelloidesErg3 and Erg6a as key enzymes to produce ergosterol, a vital constituent of fungal membranes. Absence of any of those enzymes leads to decreased ergosterol and consequently, resistance to ergosterol-binding polyenes such as amphotericin B. Particularly, losing Erg6a function pose a higher threat as the ergosterol pathway is channeled into alternative sterols similar to cholesterol, which maintain membrane permeability. As a result,erg6amutants survive within the host and disseminate the infection, indicating that Erg6a deficiency may arise during human infections and confer resistance to the most effective treatment against mucormycoses.
Identification of parthenogenesis-inducing effector proteins inWolbachia
Authors: Fricke Laura C , Lindsey Amelia RI
Published: December 2023

Bacteria in the genusWolbachiahave evolved numerous strategies to manipulate arthropod sex, including the conversion of would-be male offspring to asexually reproducing females. This so-called “parthenogenesis-induction” phenotype can be found in a number ofWolbachiastrains that infect arthropods with haplodiploid sex determination systems, including parasitoid wasps. Despite the discovery of microbe-mediated parthenogenesis more than 30 years ago, the underlying genetic mechanisms have remained elusive. We used a suite of genomic, computational, and molecular tools to identify and characterize two proteins that are uniquely found in parthenogenesis-inducingWolbachiaand have strong signatures of host-associated bacterial effector proteins. These putative parthenogenesis-inducing proteins have structural homology to eukaryotic protein domains including nucleoporins, the key insect sex-determining factor Transformer, and a eukaryotic-like serine-threonine kinase with leucine rich repeats. Furthermore, these proteins significantly impact eukaryotic cell biology in the model,Saccharomyces cerevisiae. We suggest these proteins are parthenogenesis-inducing factors and our results indicate this would be made possible by a novel mechanism of bacterial-host interaction.
The Lateral/Caudal Ganglionic Eminence Makes a Limited Contribution to Cortical Oligodendrocytes
Authors: Li Jialin , Yang Feihong , Tian Yu , Wang Ziwu , Qi Dashi , Yang Zhengang , Song Jiangang , Ding Jing , Wang Xin , Zhang Zhuangzhi
Published: December 2023

The emergence of myelinating oligodendrocytes represents a pivotal developmental milestone in vertebrates, given their capacity to ensheath axons and facilitate the swift conduction of action potentials. It is widely accepted that cortical oligodendrocyte progenitor cells (OPCs) arise from medial ganglionic eminence (MGE), lateral/caudal ganglionic eminence (LGE/CGE) and cortical radial glial cells (RGCs). Here, we used two different fate mapping strategies to challenge the established notion that the LGE generates cortical OPCs. Furthermore, we used a Cre/loxP-dependent exclusion strategy to reveal that the LGE/CGE-derived OPCs are minimal. Additionally, we showed that specifically eliminating MGE-derived OPCs leads to a significant reduction of cortical OPCs. Together, our findings indicate that the contribution of OPCs from LGE/CGE is minimal, contrary to previous beliefs. These findings provide a new view of the developmental origins of cortical OPCs and a valuable foundation for future research on both normal development and oligodendrocyte-related disease.
Quantitative Analysis of Autophagy in Single Cells: Differential Response to Amino Acid and Glucose Starvation
Authors: Martin Katie R. , Celano Stephanie L. , Sheldon Ryan D. , Jones Russell G. , MacKeigan Jeffrey P.
Published: December 2023

Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we sought to generate a quantitative catalog of autophagy across multiple stages and in single, living cells under normal growth conditions as well as in media starved specifically of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions. In addition to sharing our findings here, we provide our data as a high-quality resource for others interested in mathematical modeling or otherwise exploring autophagy in individual cells across a population.
Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence
Authors: Sha Kai , Zhang Renyaun , Maolake Aerken , Singh Shalini , Chatta Gurkamal , Eng Kevin H , Nastiuk Kent L , Krolewski John J
Published: December 2023

Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling the response to androgen-deprivation by surgical castration in genetically-engineered mouse models (GEMM) of PC, using high frequency ultrasound imaging to rigorously measure tumor volume. Castration initially causes almost all tumors to shrink in volume, but many tumors subsequently recur within 5-10 weeks. Blockade of tumor necrosis factor (TNF) signaling a few days in advance of castration surgery, using a TNFR2 ligand trap, prevents regression in a PTEN-deficient GEMM. Following tumor regression, a basal stem cell-like population within the tumor increases along with TNF protein levels. Tumor cell lines in culture recapitulate these in vivo observations, suggesting that basal stem cells are the source of TNF. When TNF signaling blockade is administered immediately prior to castration, tumors regress but recurrence is prevented, implying that a late wave of TNF secretion within the tumor, which coincides with the expression of NFkB regulated genes, drives recurrence. The inhibition of signaling downstream of one NFkB-regulated protein, chemokine C-C motif ligand 2 (CCL2), prevents post-castration tumor recurrence, phenocopying post-castration (late) TNF signaling blockade. CCL2 was originally identified as a macrophage chemoattractant and indeed at late times after castration gene sets related to chemotaxis and migration are up-regulated. Importantly, enhanced CCL2 signaling during the tumor recurrence phase coincides with an increase in pro-tumorigenic macrophages and a decrease in CD8 T cells, suggesting that recurrence is driven at least in part by tumor immunosuppression. In summary, we demonstrate that a therapy-induced switch in TNF signaling, a consequence of the increased stem cell-like character of the residual tumor cells surviving ADT, induces an immunosuppressive tumor microenvironment and concomitant tumor recurrence.
CpG Island Definition and Methylation Mapping of the T2T-YAO Genome
Authors: Xiao Ming , Wei Rui , Yu Jun , Gao Chujie , Yang Fengyi , Zhang Le
Published: December 2023

Precisely defining and mapping all cytosine positions and their clusters, known as CpG islands (CGIs), as well as their methylation status are pivotal for genome-wide epigenetic studies, especially when population-centric reference genomes are ready for timely application. Here we first align the two high-quality reference genomes, T2T-YAO and T2T-CHM13, from different ethnic backgrounds in a base-by-base fashion and compute their genome-wide density-defined and position-defined CGIs. Second, mapping some representative genome-wide methylation data from selected organs onto the two genomes, we find that there are about 4.7–5.8% sequence divergency of variable categories depending on quality cutoffs. Genes among the divergent sequences are mostly associated with neurological functions. Moreover, CGIs associated with the divergent sequences are significantly different with respect to CpG density and observed CpG/expected CpG (O/E) ratio between the two genomes. Finally, we find that the T2T-YAO genome not only has a greater CpG site coverage than that of the T2T-CHM13 genome when whole-genome bisulfite sequencing (WGBS) data from the European and American populations are mapped to each reference, but also show more hyper-methylated CpG sites as compared to the T2T-CHM13 genome. Our study suggests that future genome-wide epigenetic studies of the Chinese populations rely on both acquisition of high-quality methylation data and subsequent precision CGI mapping based on the Chinese T2T reference.
Genomic plasticity is a blueprint of diversity inSalmonellalineages
Authors: Kushwaha Simran Krishnakant , Anand Abhirath , Wu Yi , Ávila Hugo Leonardo , Sicheritz-Pontén Thomas , Millard Andrew , Marathe Sandhya Amol , Nobrega Franklin L.
Published: December 2023

The flexible genome, organised in regions of genomic plasticity (RGP), serves as a potent facilitator of the dynamic evolution of bacterial genomes through gene acquisition and loss. Here we explored the genomic plasticity acrossSalmonellalineages, revealing a purposeful, non-random integration pattern of pathogenicity-related gene clusters into specific RGP. Noteworthy examples include the correlation between the type I-E CRISPR-Cas system, gold tolerance, and specific RGP. The scattered prevalence of RGP acrossSalmonellalineages profoundly shapes the pathogenicity makeup ofSalmonellastrains. The preferences of RGP seem guided by conserved flanking genes that likely share regulatory and functional coordination. For example, metal resistance genes are predominant in RGP positioned near stress resistance genes, indicating a regulatory network to efficiently counter stressors. Additionally, we observed that different plasmid incompatibility types and prophage genera carry distinct pathogenicity genes. Similar to RGP, their distribution acrossSalmonellalineages plays a critical role in defining pathogenicity. By uncovering these intricate connections among gene clusters, RGP, mobile genetic elements, and pathogenic attributes, our study offers novel insights into the evolutionary trajectory ofSalmonellaand holds promise for predicting future adaptations and developing targeted interventions against infections.
Paracrine effects of the senescence-associated secretory phenotype decrease cancer cell adhesion
Authors: Cole Aidan R. , Buj Raquel , Elhaw Amal Taher , Uboveja Apoorva , Tangudu Naveen , Oesterreich Steffi , Stallaert Wayne , Hempel Nadine , Aird Katherine M.
Published: December 2023

High grade serous ovarian cancer (HGSOC) is the most lethal gynecological cancer. Platinumbased therapies such as cisplatin are standard-of-care for HGSOC patients; however, the majority of HGSOCs initially treated with cisplatin will recur with widespread disseminated disease. Cisplatin induces cellular senescence, a stable cell cycle arrest. Although they are non-proliferative, senescent cells secrete a complex mix of cytokines and small molecules, named the senescence associated secretory phenotype (SASP), that have been shown to have pro-tumorigenic effects. To investigate how the SASP contributes to HGSOC progression, we used conditioned media from cisplatin therapy-induced senescent cells to culture naïve HGSOC spheroids. We report that while the SASP does not affect spheroid formation, the adhesion of cells within spheroids is altered, leading to cell detachment from spheroids. Interestingly, our data indicate that this occurs in an MMP-independent manner. Analysis of RNA-Seq samples indicates many adhesion-related genes and adhesion factors are transcriptionally downregulated by the SASP, particularly fibronectin and integrins, which was validated by immunofluorescence in spheroids. These data reveal that senescent cells contribute to a transcriptional program in nearby cancer cells in a paracrine fashion that decreases their adhesion, which may contribute to tumor dissemination.
A red light-induced genetic system for control of extracellular electron transfer
Authors: Zhao Fengjie , Niman Christina M. , Ostovar Ghazaleh , Chavez Marko S. , Atkinson Joshua T. , Bonis Benjamin M. , Gralnick Jeffrey A. , El-Naggar Mohamed Y. , Boedicker James Q.
Published: December 2023

Optogenetics is a powerful tool for spatiotemporal control of gene expression. Several light-inducible gene regulators have been developed to function in bacteria, and these regulatory circuits have been ported into new host strains. Here, we developed and adapted a red light-inducible transcription factor forShewanella oneidensis. This regulatory circuit is based on the iLight optogenetic system, which controls gene expression using red light. Promoter engineering and a thermodynamic model were used to adapt this system to achieve differential gene expression in light and dark conditions within aS. oneidensishost strain. We further improved the iLight optogenetic system by adding a repressor to invert the genetic circuit and activate gene expression under red light illumination. The inverted iLight genetic circuit was used to control extracellular electron transfer (EET) withinS. oneidensis. The ability to use both red and blue light-induced optogenetic circuits simultaneously was demonstrated. Our work expands the synthetic biology toolbox ofShewanella, which could facilitate future advances in applications with electrogenic bacteria.
Multi-omics framework to reveal the molecular determinants of fermentation performance in wine yeast populations
Authors: de Celis Miguel , Ruiz Javier , Benitez-Dominguez Belen , Vicente Javier , Tomasi Sandra , Izquierdo-Gea Sergio , Rozés Nicolás , Ruiz-de-Vila Candela , Gombau Jordi , Zamora Fernando , Barroso Alicia , Terron-Camero Laura C. , Andres-Leon Eduardo , Santos Antonio , Belda Ignacio
Published: December 2023

Background

Connecting the composition and function of industrial microbiomes is a major aspiration in microbial biotechnology. Here, we address this question in wine fermentation, a model system where the diversity and functioning of fermenting yeast species is determinant of the flavor and quality of the resulting wines.

Results

First, we surveyed yeast communities associated with grape musts collected across wine appellations, revealing the importance of environmental (i.e., biogeography) and anthropic factors (i.e., farming system) in shaping community composition and structure. Then, we assayed the fermenting yeast communities in synthetic grape must under common winemaking conditions. The dominating yeast species defines the fermentation performance and metabolite profile of the resulting wines, and it is determined by the initial fungal community composition rather than the imposed fermentation conditions. Yeast dominance also had a more pronounced impact on wine meta-transcriptome than fermentation conditions. We unveiled yeast-specific transcriptomic profiles, leveraging different molecular functioning strategies in wine fermentation environments. We further studied the orthologs responsible for metabolite production, revealing modules associated with the dominance of specific yeast species. This emphasizes the unique contributions of yeast species to wine flavor, here summarized in an array of orthologs that defines the individual contribution of yeast species to wine ecosystem functioning.

Conclusions

Our study bridges the gap between yeast community composition and wine metabolite production, providing insights to harness diverse yeast functionalities with the final aim to producing tailored high-quality wines.
Histone marks enable formation of immiscible phase-separated chromatin compartments
Authors: Sun Wenjing , Wang Jiacheng , Liu Wenqian , Tang Baixue , Qu Hongyuan , Wang Jianwei , Li Haitao , Xie Wei , Li Pilong
Published: December 2023

Eukaryotic chromatin is organized into compartments for gene expression regulation, but the underlying mechanisms remain unclear. Here, we demonstrate that multivalent H3K27me3 and its reader, CBX7-PRC1 complex, regulate facultative heterochromatin via a phase separation mechanism, similar to constitutive heterochromatin1. Facultative and constitutive heterochromatin represent distinct, coexisting condensates in nuclei.In vitro,H3K27me3- and H3K9me3-marked nucleosomal arrays and their reader complexes can phase separate into immiscible condensates that are analogous to the relationship between facultative and constitutive heterochromatinin vivo. Moreover, overexpression of CBX7-PRC1 causes aberrant chromatin compartmentalizationin vivoas demonstrated by H3K9me3 CUT&Tag and up-regulation of genes related to cancer such as acute myeloblastic leukemia (AML). CBX7 inhibitor effectively inhibits cancer cell proliferation possibly through phase separation-mediated compartment reorganization. Our data demonstrated how the specificity of compartmentalization is achieved based on the formation of immiscible phase-separated condensates, and offer novel epigenetic mechanistic insights into tumor development.
CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy
Authors: Zaninello Marta , Schlegel Tim , Nolte Hendrik , Pirzada Mujeeb , Savino Elisa , Barth Esther , Wüstenberg Hauke , Uddin Tesmin , Wolff Lisa , Wirth Brunhilde , Lehmann Helmar C. , Cioni Jean-Michel , Langer Thomas , Rugarli Elena I.
Published: December 2023

Transport and local translation of mRNAs in distal axonal compartments are essential for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects mitochondria from damage during their long journey along the axon, however the regulatory factors involved are largely unknown. Here, we show that CLUH, a cytosolic protein that binds mRNAs encoding mitochondrial proteins, is essential for preventing axonal degeneration of spinal motoneurons and maintaining motor behavior in the mouse. We demonstrate that CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The absence of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits specifically in the growth cone. CLUH binds ribosomal subunits, translation initiation and ribosome recycling components, and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the growth cone and translation defects in CLUH-deficient motoneurons. In conclusion, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which are essential for their development and long-term integrity and function.
Small-molecule activators of a bacterial signaling pathway inhibit virulence
Authors: Mansour Kathryn E. , Qi Yunchuan , Yan Mingdi , Ramström Olof , Priebe Gregory P. , Schaefers Matthew M.
Published: December 2023

TheBurkholderiagenus encompasses multiple human pathogens, including potential bioterrorism agents, that are often extensively antibiotic resistant. The FixLJ pathway inBurkholderiais a two-component system that regulates virulence. Previous work showed thatfixLJmutations arising during chronic infection confer increased virulence while decreasing the activity of the FixLJ pathway. We hypothesized that small-molecule activators of the FixLJ pathway could serve as anti-virulence therapies. Here, we developed a high-throughput assay that screened over 28,000 compounds and identified 11 that could specifically active the FixLJ pathway. Eight of these compounds, denotedBurkholderiaFixActivator (BFA) 1-8, inhibited the intracellular survival ofBurkholderiain THP-1-dervived macrophages in afixLJ-dependent manner without significant toxicity. One of the compounds, BFA1, inhibited the intracellular survival in macrophages of multipleBurkholderiaspecies. Predictive modeling of the interaction of BFA1 withBurkholderiaFixL suggests that BFA1 binds to the putative ATP/ADP binding pocket in the kinase domain, indicating a potential mechanism for pathway activation. These results indicate that small-molecule FixLJ pathway activators are promising anti-virulence agents forBurkholderiaand define a new paradigm for antibacterial therapeutic discovery.
Selective Vulnerability of Parvocellular Oxytocin Neurons in Social Dysfunction
Authors: Tsurutani Masafumi , Goto Teppei , Hagihara Mitsue , Irie Satsuki , Miyamichi Kazunari
Published: December 2023

Selective vulnerability offers a conceptual framework for understanding neurodegenerative disorders, such as Parkinson’s disease, where specific neuronal types are selectively affected while adjacent ones are spared. The applicability of this framework to neurodevelopmental disorders remains uncertain, particularly those characterized by atypical social behaviors such as autism spectrum disorder. Here, employing a single-cell transcriptome analysis in mice, we show that an embryonic disturbance known to induce social dysfunction preferentially impairs gene expressions crucial for neural functions in parvocellular oxytocin (OT) neurons—a subtype linked to social rewards—while neighboring cell types experience a lesser impact. Chemogenetic stimulation of OT neurons at the neonatal stage ameliorated social deficits in early adulthood, concurrent with a cell-type-specific sustained recovery of the pivotal gene expressions within parvocellular OT neurons. Collectively, our data shed light on the transcriptomic selective vulnerability within the hypothalamic social behavioral center and provide a potential therapeutic target through specific neonatal neurostimulation.
Do peers really influence doctors' knowledge contribution behavior? Evidence from online health communities
Authors: Lei Licai , Hu Shiyi
Published: December 2023

Purpose

The online health community's success depends on doctors' active participation, so it is essential to understand the factors that affect doctors' knowledge contribution behavior in the online health communities. From the perspective of peer effect, this paper discusses the influence of focal doctors' peers on focal doctors' knowledge contribution behavior and the mechanism behind it. This paper aims to solve these problems.

Design/methodology/approach

Empirical data of 1,938 doctors were collected from a Chinese online health community, and propensity score matching and ordinary least squares were employed to verify the proposed theoretical model.

Findings

The results show that the presence of focal doctors' peers in online health communities has a positive effect on the knowledge contribution behavior of focal doctors, and the economic returns and social returns of focal doctors' peers have a significant mediating effect.

Originality/value

This paper discusses focal doctors' knowledge contribution behavior from the perspective of peer effect. It enhances the understanding of focal doctors' behavior in the online health communities by exploring the mediating role of their peers' economic and social returns. The results of this paper extend the research in the field of peer effect and online health and provide management implications and suggestions for online health platforms and doctors.