bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and pathological characteristics and expression of related molecules in patients with airway disseminated lung adenocarcinoma
Authors: Luan Wei , Liu Shuai , Zhang Kai , He Yin-Zai
Published: June 2024

Objective

Lung adenocarcinoma exhibits diverse genetic and morphological backgrounds, in addition to considerable differences in clinical pathology and molecular biological characteristics. Among these, the phenomenon of spread through air space (STAS), a distinct mode of lung cancer infiltration, has rarely been reported. Therefore, this study aimed to explore the relationship between STAS tumor cells and the clinical and molecular characteristics of patients with lung adenocarcinoma, as well as their impact on prognosis.

Methods

This study included 147 patients who were diagnosed with lung adenocarcinoma at the Inner Mongolia Autonomous Region Cancer Institute between January 2014 and December 2017. Surgical resection specimens were retrospectively analyzed. Using univariate and multivariate Cox analyses, we assessed the association between STAS and the clinicopathological features and molecular characteristics of patients with lung adenocarcinoma. Furthermore, we investigated the effects on patient prognosis. In addition, we developed a column–line plot prediction model and performed internal validation.

Results

Patients with positive STAS had a significantly higher proportion of tumors with a diameter ≥2 cm, with infiltration around the pleura, blood vessels, and nerves, and a pathological stage >IIB than in STAS-negative patients (P < 0.05). Cox multivariate survival analysis revealed that clinical stage, STAS status, tumor size, and visceral pleural invasion were independent prognostic factors influencing the 5-year progression-free survival in patients with lung adenocarcinoma. The predictive values and P values from the Hosmer-Lemeshow test were 0.8 and 0.2, respectively, indicating no statistical difference. Receiver operating characteristic curve analysis demonstrated areas under the curve of 0.884 and 0.872 for the training and validation groups, respectively. The nomogram model exhibited the best fit with a value of 192.09.

Conclusions

Clinical stage, pleural invasion, vascular invasion, peripheral nerve invasion, tumor size, and necrosis are independent prognostic factors for patients with STAS-positive lung adenocarcinoma. The nomogram based on the clinical stage, pleural invasion, vascular invasion, peripheral nerve invasion, tumor size, and necrosis showed good accuracy, differentiation, and clinical practicality.
TCGA-based analysis of oncogenic signaling pathways underlying oral squamous cell carcinoma
Authors: Gao Xing , Liu Dan-Dan , Liu Jin-Zhong , Wang Rui
Published: June 2024

Background

Oral squamous cell carcinoma (OSCC) represents a prevalent malignancy in the oral and maxillofacial area, having a considerable negative impact on both the quality of life and overall survival of affected individuals. Our research endeavors to leverage bioinformatic approaches to elucidate oncogenic signaling pathways, with the ultimate goal of gaining deeper insights into the molecular underpinnings of OSCC pathogenesis, and thus laying the groundwork for the development of more effective therapeutic and preventive strategies.

Methods

Differential expression analysis was performed on mRNA data from tumor and normal tissue groups to identify genes associated with OSCC, using The Cancer Genome Atlas database. Predictions of oncogenic signaling pathways linked to differentially expressed mRNAs were made, and these results were presented visually using R software, using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichments.

Results

GO and KEGG analyses of 2938 differentially expressed genes in OSCC highlighted their significant involvement in various biological processes. Notably, these processes were related to the extracellular matrix, structural organization, connective tissue development, and cell cycle regulation.

Conclusions

The comprehensive exploration of gene expression patterns provides valuable insights into potential oncogenic mechanisms in OSCC.
Resource sustainability and challenges in the supply chain: implications for infection prevention
Authors: Mehrotra Preeti , Desai Angel
Published: June 2024

Purpose of review

Infection prevention and control practices remain the bedrock of healthcare associated infection prevention and outbreak and epidemic control efforts. However, issues in supply chain management can hinder these efforts, as exemplified by various public health emergencies. This review explores the key role of supply chains in infection prevention and explores specific challenges.

Recent findings

In all of the critical components of infection prevention and control – hand hygiene, personal protective equipment, sterile supplies, environmental disinfection, and waste management – disruptions in supply chains have led to limited availability and dissemination.

Strategies to mitigate these resource constraints in the inter-epidemic period will also be highlighted. The infection prevention workforce is well poised to inform supply chain dynamics. Without robust and adequate supply chains, infection prevention and control efforts suffer which perpetuates healthcare-associated infections, clusters, and epidemics.
Infrapopliteal Endovascular Interventions for Claudication Are Associated with Poor Long-Term Outcomes in Medicare-Matched Registry Patients
Authors: Bose Sanuja , McDermott Katherine M. , Dun Chen , Mao Jialin , Solomon Alex J. , Black James H. , Columbo Jesse A. , Conte Michael S. , Deery Sarah E. , Goodney Philip P. , Kalathiya Rohan , Kalbaugh Corey A. , Siracuse Jeffrey J. , Woo Karen , Makary Martin A. , Hicks Caitlin W.
Published: June 2024

Background:

There are limited data supporting or opposing the use of infrapopliteal peripheral vascular interventions (PVI) for the treatment of claudication.

Objectives:

We aimed to evaluate the association of infrapopliteal PVI with long-term outcomes compared with isolated femoropopliteal PVI for the treatment of claudication.

Methods:

We conducted a retrospective analysis of all patients in the Medicare-matched Vascular Quality Initiative database who underwent an index infrainguinal PVI for claudication from January 2004-December 2019 using Cox proportional hazards models.

Results:

Of 14,261 patients (39.9% female; 85.6% age ≥65 years, 87.7% non-Hispanic white) who underwent an index infrainguinal PVI for claudication, 16.6% (N=2,369) received an infrapopliteal PVI. The median follow-up after index PVI was 3.7 years (IQR 2.1-6.1). Compared to patients who underwent isolated femoropopliteal PVI, patients receiving any infrapopliteal PVI had a higher 3-year cumulative incidence of conversion to CLTI (33.3% vs. 23.8%; P<0.001); repeat PVI (41.0% vs. 38.2%; P<0.01); and amputation (8.1% vs. 2.8%; P<0.001). After risk-adjustment, patients undergoing infrapopliteal PVI had a higher risk of conversion to CLTI (aHR 1.39, 95% CI, 1.25-1.53); repeat PVI (aHR 1.10, 95% CI, 1.01-1.19); and amputation (aHR 2.18, 95% CI, 1.77-2.67). Findings were consistent after adjusting for competing risk of death; in a 1:1 propensity-matched analysis; and in subgroup analyses stratified by TASC disease, diabetes, and end-stage kidney disease.

Conclusions:

Infrapopliteal PVI is associated with worse long-term outcomes than femoropopliteal PVI for claudication. These risks should be discussed with patients.
Surgical Intelligence Can Lead to Higher Adoption of Best Practices in Minimally Invasive Surgery
Authors: Fried Gerald M. , Ortenzi Monica , Dayan Danit , Nizri Eran , Mirkin Yuval , Maril Sari , Asselmann Dotan , Wolf Tamir
Published: June 2024

Objective:

To examine the use of surgical intelligence for automatically monitoring critical view of safety (CVS) in laparoscopic cholecystectomy (LC) in a real-world quality initiative.

Background:

Surgical intelligence encompasses routine, artificial intelligence-based capture and analysis of surgical video, and connection of derived data with patient and outcomes data. These capabilities are applied to continuously assess and improve surgical quality and efficiency in real-world settings.

Methods:

Laparoscopic cholecystectomies conducted at 2 general surgery departments between December 2022 and August 2023 were routinely captured by a surgical intelligence platform, which identified and continuously presented CVS adoption, surgery duration, complexity, and negative events. In March 2023, the departments launched a quality initiative aiming for 75% CVS adoption.

Results:

Two hundred seventy-nine procedures were performed during the study. Adoption increased from 39.2% in the 3 preintervention months to 69.2% in the final 3 months (P < 0.001). Monthly adoption rose from 33.3% to 75.7%. Visualization of the cystic duct and artery accounted for most of the improvement; the other 2 components had high adoption throughout. Procedures with full CVS were shorter (P = 0.007) and had fewer events (P = 0.011) than those without. OR time decreased following intervention (P = 0.033).

Conclusions:

Surgical intelligence facilitated a steady increase in CVS adoption, reaching the goal within 6 months. Low initial adoption stemmed from a single CVS component, and increased adoption was associated with improved OR efficiency. Real-world use of surgical intelligence can uncover new insights, modify surgeon behavior, and support best practices to improve surgical quality and efficiency.
Mixed ctDNA dynamics and decreased detection rates in early-stage lung cancer patients during radiation treatment
Authors: Boniface Christopher , Baker Kathryn , Deig Christopher , Halsey Carol , Kelley Taylor , Rahmani Ramtin , Tormoen Garth , Spellman Paul T , Nabavizadeh Nima
Published: June 2024

Quantification and detection of circulating tumor DNA (ctDNA) has been used to identify the presence of cancers. Ablative radiation therapy kills tumor cells to reduce tumor burden and it follows that these dying tumor cells could lead to increased ctDNA abundance. We carried out deep, error-corrected sequencing of cell-free DNA collected serially from 12 stage I, and 2 stage II/III non-small cell lung cancer (NSCLC) patients undergoing external-beam radiation treatment (EBRT) after initial diagnosis. We found that ctDNA detection rates decreased at the first blood draw as compared to baseline (43% to 7% of patients). Total ctDNA abundance decreased in 6 patients and increased in 5 patients between those same blood draws, with one patient showing evidence of tumoral heterogeneity. Both patients with stage II/III disease had the largest increases in ctDNA abundance from baseline. Multiple blood draws improved ctDNA detection rates from 43% to 50% with a second blood draw and to 71% with 4 blood draws. Additionally, EGFR mutations were detectable in 6 patients during EBRT that were not detected prior to treatment. Taken together, these results provide an early-stage NSCLC counterpoint to previous work that reported improved ctDNA detection after radiation therapy in more advanced disease.
Competing Risk Survival analysis of time to in-hospital mortality or Recovery among Covid-19 Patients in South-East Ethiopia: a hospital-based multisite study
Authors: Wordofa Addis , Demissie Ayalneh , Kalu Abdurehman , Tune Abdurehman , Suleiman Mohammed , Kibret Abay , Abera Zerihun , Mulugeta Yonas
Published: June 2024

Background

To date, survival data on risk factors for COVID-19 mortality in south- Ethiopia is limited, and none of the published survival studies have used a competing risk approach. This study aims to identify risk factors for in-hospital mortality in COVID-19 patients hospitalized at one of the six hospitals in southeast -Ethiopia, considering recovery as a competing risk.

Methods

This observational multisite study included a medical record of 827 confirmed SARS-CoV-2 cases hospitalized at one of the six hospitals in southeast-Ethiopia from October 1, 2022 to May 31, 2023. We compiled data on the patients’ socio-demographic characteristics, clinical manifestation, comorbidity, treatment status, treatment outcomes, and length of stay. We performed a Cox regression analysis for competing risks, presenting cause-specific hazard ratios (HRcs) for the effect of preselected factors on the absolute risk of death and recovery.

Results

827 patients were included (51.9% male; median age 50 years, IQR: 38—65). Patients were hospitalized for a median duration of 5 days (IQR: 1—7); 139 (17%) of them died, while 516 (62%) were recovered and discharged alive, the rest 172 (21%) were censored. Patients with higher age (HRcs 2.62, 95% CI 1.29—5.29), immune- compromised state (HRcs 1.46, 95% CI 1.08—1.98) had increased risk of death, whereas male sex paradoxically (HRcs 0.45, 95% CI 0.22—0.91) associated with decreased risk of death. We found no increased mortality risk in diabetes patients.

Conclusion

This competing risk survival analysis allows us to corroborate specific pattern of risk factors about COVID-19 mortality and its progression among different groups of individuals (differentiated by age and immune-compromised state). 62% presenting cases recovered within a median duration of 5 days; where as 17% die within the first 72 hours, most with immune-compromised conditions. This should be considered while planning and allocating the distribution of care services for effective health service delivery
The Relationships of Resting-state Brain Entropy (BEN), Ovarian Hormones and Behavioral Inhibition and Activation Systems (BIS/BAS)
Authors: Song Dong-Hui , Wang Ze
Published: June 2024

Entropy measures the irregularity or complexity of a system. Recent research on brain entropy (BEN) based on resting-state fMRI has provided complementary information to other metrics such as low-frequency fluctuations and cerebral blood flow. It has been established that neural plasticity, both pharmacological and nonpharmacological, as well as brain stimulation can influence BEN. However, it remains unknown whether BEN can reflect the effects of hormones. Furthermore, recent studies have indicated that ovarian hormones influence both the behavioral inhibition and activation systems. In our study, we utilized open-access available data from OpenNeuro to investigate the effects of ovarian hormones on BEN and their impact on BIS/BAS.

Our results indicated a negative correlation between progesterone (PROG) and BEN in the frontal-parietal network and limbic system, while BEN showed a significant positive correlation with BAS-drive in the DLPFC. Additionally, a significant negative correlation was observed between PROG and BAS-drive. Further analysis revealed that DLPFC BEN mediates the negative correlation between PROG and BAS-drive. This suggests that PROG reduces BAS-drive by increasing the executive and inhibitory functions of DLPFC. We also analyzed the FC between DLPFC and the whole brain. DLPFC-IPL FC showed a significant positive correlation with BAS-drive, while DLPFC-LOFC FC exhibited a significant negative correlation with BAS-fun-seeking. Moreover, DLPFC-AG FC demonstrated a significant positive correlation with BAS-rewards. These results are consistent with the relationship between executive functions of the frontal-parietal network and impulsivity representation of BAS.

Our study is the first to demonstrate that BEN can also reflect the impact of hormones on brain function. Additionally, we identified that the negative correlation between PROG and BAS-drive is mediated by left DLPFC BEN, providing new insights into our understanding of the effects of PROG on the brain and behavior.
Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia
Authors: Goussakov Ivan , Synowiec Sylvia , Fabres Rafael Bandeira , Almeida Gabriela Dias , Takada Silvia Honda , Aksenov Daniil , Drobyshevsky Alexander
Published: June 2024

Background

Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI.

Methods

C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13. Behavioral tests were conducted at P41-P50 to assess animal activity and motor learning.

Results

Adult mice after neonatal IH exhibited hyperactivity in open field test and impaired motor learning in complex wheel tasks. Patch clamp and evoked field potential electrophysiology revealed increased glutamatergic transmission accompanied by elevation of tonic inhibition.

A decreased synaptic inhibitory drive was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo in the motor cortex with selective GABAAreceptor inhibitor picrotoxin injection, as well as by the decreased interneuron density at P13. There was also an increased tonic depolarizing effect of picrotoxin after IH on principal cells’ membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase after picrotoxin injection in the IH group.

Conclusions

Increased excitatory glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes, including impaired motor learning and hyperactivity. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH. The increased tonic inhibition, presumably due to tonic extrasynaptic GABA receptor drive, may be compensatory to the elevated excitatory glutamatergic transmission.
Comparative connectomics of the descending and ascending neurons of theDrosophilanervous system: stereotypy and sexual dimorphism
Authors: Stürner Tomke , Brooks Paul , Capdevila Laia Serratosa , Morris Billy J. , Javier Alexandre , Fang Siqi , Gkantia Marina , Cachero Sebastian , Beckett Isabella R. , Champion Andrew S. , Moitra Ilina , Richards Alana , Klemm Finja , Kugel Leonie , Namiki Shigehiro , Cheong Han S.J. , Kovalyak Julie , Tenshaw Emily , Parekh Ruchi , Schlegel Philipp , Phelps Jasper S. , Mark Brandon , Dorkenwald Sven , Bates Alexander S. , Matsliah Arie , Yu Szi-chieh , McKellar Claire E. , Sterling Amy , Seung Sebastian , Murthy Mala , Tuthill John , Lee Wei-Chung A. , Card Gwyneth M. , Costa Marta , Jefferis Gregory S.X.E. , Eichler Katharina
Published: June 2024

In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control.

Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system ofDrosophilaand compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations.

We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.
Cross-species modeling of plant genomes at single nucleotide resolution using a pre-trained DNA language model
Authors: Zhai Jingjing , Gokaslan Aaron , Schiff Yair , Berthel Ana , Liu Zong-Yan , Lai Wei-Yun , Miller Zachary R , Scheben Armin , Stitzer Michelle C , Romay Cinta , Buckler Edward S. , Kuleshov Volodymyr
Published: June 2024

Interpreting function and fitness effects in diverse plant genomes requires transferable models. Language models (LMs) pre-trained on large-scale biological sequences can learn evolutionary conservation and offer cross-species prediction better than supervised models through fine-tuning limited labeled data. We introduce PlantCaduceus, a plant DNA LM based on the Caduceus and Mamba architectures, pre-trained on a curated dataset of 16 Angiosperm genomes. Fine-tuning PlantCaduceus on limited labeled Arabidopsis data for four tasks, including predicting translation initiation/termination sites and splice donor and acceptor sites, demonstrated high transferability to 160 million year diverged maize, outperforming the best existing DNA LM by 1.45 to 7.23-fold. PlantCaduceus is competitive to state-of-the-art protein LMs in terms of deleterious mutation identification, and is threefold better than PhyloP. Additionally, PlantCaduceus successfully identifies well-known causal variants in both Arabidopsis and maize. Overall, PlantCaduceus is a versatile DNA LM that can accelerate plant genomics and crop breeding applications.
Protein Sequence Domain Annotation using Language Models
Authors: Sarkar Arpan , Krishnan Kumaresh , Eddy Sean R.
Published: June 2024

Abstract

Protein function inference relies on annotating protein domains via sequence similarity, often modeled through profile Hidden Markov Models (profile HMMs), which capture evolutionary diversity within related domains. However, profile HMMs make strong simplifying independence assumptions when modeling residues in a sequence. Here, we introduce PSALM (Protein Sequence Annotation using Language Models), a hierarchical approach that relaxes these assumptions and uses representations of protein sequences learned by protein language models to enable high-sensitivity, high-specificity residue-level protein sequence annotation. We also develop the Multi-Domain Protein Homology Benchmark (MDPH-Bench), a benchmark for protein sequence domain annotation, where training and test sequences have been rigorously split to share no similarity between any of their domains at a given threshold of sequence identity. Prior benchmarks, which split one domain family at a time, do not support methods for annotating multi-domain proteins, where training and test sequences need to have multiple domains from different families. We validate PSALM’s performance on MDPH-Bench and highlight PSALM as a promising alternative to HMMER, a state-of-the-art profile HMM-based method, for protein sequence annotation.
Evaluation in mice of cell-free produced CT584 as a Chlamydia vaccine antigen
Authors: Hoang-Phou Steven , Pal Sukumar , Slepenkin Anatoli , Abisoye-Ogunniyun Abisola , Zhang Yuliang , Gilmore Sean F. , Shelby Megan , Bourguet Feliza , Mohagheghi Mariam , Noy Aleksandr , Rasley Amy , de la Maza Luis M. , Coleman Matthew A.
Published: June 2024

Chlamydia trachomatisis the most prevalent bacterial sexually transmitted pathogen worldwide. Since chlamydial infection is largely asymptomatic with the potential for serious complications, a preventative vaccine is likely the most viable long-term answer to this public health threat. Cell-free protein synthesis (CFPS) utilizes the cellular protein manufacturing machinery decoupled from the requirement for maintaining cellular viability, offering the potential for flexible, rapid, and de-centralized production of recombinant protein vaccine antigens. Here, we use CFPS to produce the putative chlamydial type three secretion system (T3SS) needle-tip protein, CT584, for use as a vaccine antigen in mouse models. High-speed atomic force microscopy (HS-AFM) imaging and computer simulations confirm that CFPS-produced CT584 retains a native-like structure prior to immunization. Female mice were primed with CT584 adjuvanted with CpG-1826 intranasally (i.n.) or CpG-1826 + Montanide ISA 720 intramuscularly (i.m.), followed four-weeks later by an i.m. boost before respiratory challenge with 104inclusion forming units (IFU) ofChlamydia muridarum. Immunization with CT584 generated robust antibody responses but weak cell mediated immunity and failed to protect against i.n. challenge as demonstrated by body weight loss, increased lungs’ weights and the presence of high numbers of IFUs in the lungs. While CT584 alone may not be the ideal vaccine candidate, the speed and flexibility with which CFPS can be used to produce other potential chlamydial antigens makes it an attractive technique for antigen production.
Genome-wide temporal gene expression reveals a post-reproductive shift in the nematodeC. briggsae
Authors: Berg Wouter van den , Gupta Bhagwati P
Published: June 2024

C. briggsaeoffers a robust system for comparative investigations of genetic pathways that affect physiological processes. One key process, reproduction, significantly impacts longevity due to its high energetic cost, which limits resources for somatic maintenance. Long-lived mutants often exhibit reproductive impairments, and studies inC. eleganshave demonstrated that germline mutations and complete germline removal can promote longevity, underscoring the link between reproduction and aging. We are interested in identifying genes and biological processes affected during the reproductive and post-reproductive periods inC. briggsae. To achieve this, we conducted whole-genome transcriptome profiling on animals at various adult stages. analysis of differentially expressed (DE) genes revealed that the majority were downregulated during the reproductive period. Interestingly, this trend reversed post-reproduction, with three-quarters of the genes upregulated—a phenomenon we termed the ‘reproductive shift’. A similar analysis inC. elegansalso showed a downregulation bias during the reproductive period, but the reproductive shift was absent. Further examination ofC. briggsaeDE genes showed enrichment in processes related to the matrisome, muscle development and function during the reproductive period. Post-reproductive downregulated genes were enriched in DNA damage repair, stress response, and immune response. Additionally, terms related to fatty acid metabolism, catabolism, and transcriptional regulation exhibited complex patterns, with different biological processes being up or downregulated between the reproductive and post-reproductive stages. Overall, our transcriptomic data provides a valuable resource for cross-sectional comparative studies of reproductive and post-reproductive changes in nematodes. Additionally, the findings prompt similar studies in other animal models thereby advancing our understanding of genetic pathways affecting reproduction and aging.
An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer
Authors: Li Kaiyi , Liu Chang , Li Chao , Zhang Ting , Zhao Tian , Zhang Dong , Wu Hainan , Liu Yuhan , Wang Shuai , Yang Yingshun , Lin Baobao , Wang Wenyan , Wang Jun , Sui Xizhao , Chen Xiaofang , Liu Peng
Published: June 2024

Deciphering the interactions between tumor micro- and systemic immune macro-environment is essential for developing more effective cancer diagnosis and treatment strategies. Here, we established a gel-liquid interface (GLI) co-culture of lung cancer organoids (LCOs) and paired peripheral blood mononuclear cells (PBMCs), featuring with enhanced interactions of immune cells and tumor organoids, to mimic thein vivosystemic anti-tumor immunity induced by immune checkpoint inhibitors (ICI). The co-culture model recapitulates thein vivoICI-induced T cell recruitment and subsequent tumor regression, predicting the clinical results precisely. We demonstrated that circulating tumor-reactive T cells, which are effector memory-like with high expression levels ofGNLY, CD44andCD9,can serve as an indicator of the immunotherapy efficacy. Interestingly, enhanced inflammatory signaling in blood T cells is accompanied with prompted exhaustion and compromised anti-tumor function, when encountering with organoids. Our findings suggest that the GLI co-culture can be used for developing diagnostic strategies for precision immunotherapies as well as understanding the underlying mechanisms.

Summary figure
ProToDeviseR: an automated protein topology scheme generator
Authors: Petrov Petar B. , Izzi Valerio
Published: June 2024

Motivation

Amino acid sequence characterization is a fundamental part of virtually any protein analysis, and creating concise and clear protein topology schemes is of high importance in proteomics studies. Although numerous databases and prediction servers exist, it is challenging to incorporate data from various, and sometimes contending, resources into a publication-ready scheme.

Results

Here, we present the Protein Topology Deviser R package (ProToDeviseR) for the automatic generation of protein topology schemes from database accession numbers, raw results from multiple prediction servers, or a manually prepared table of features. The application offers a graphical user interface, implemented in R Shiny, hosting an enhanced version of Pfam’s domains generator for the rendering of visually appealing schemes. Results show that ProToDeviseR can easily and quickly generate topology schemes by interrogating UniProt or NCBI GenPept databases and elegantly combine features from various resources.

Availability

Source code (https://github.com/izzilab/protodeviser) is available under GPLv3 license; the tool is also accessible for online use (https://matrinet.shinyapps.io/protodeviser/), without the need of installation.
Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states
Authors: Jedrasiak-Cape Izabela , Rybicki-Kler Chloe , Brooks Isla , Ghosh Megha , Brennan Ellen K.W. , Kailasa Sameer , Ekins Tyler G. , Rupp Alan , Ahmed Omar J.
Published: June 2024

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type – the low-rheobase (LR) neuron – has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.
PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance
Authors: Chen Zhiyi , Inague Alex , Kaushal Kamini , Fazeli Gholamreza , N Xavier da Silva Thamara , Ferreira dos Santos Ancely , Cheytan Tasneem , Porto Freitas Florencio , Yildiz Umut , Gasparello Viviani Lucas , Santiago Lima Rodrigo , Peglow Pinz Mikaela , Medeiros Isadora , Geronimo Pires Alegria Thiago , Pereira da Silva Railmara , Regina Diniz Larissa , Weinzweig Simon , Klein-Seetharaman Judith , Trumpp Andreas , Manas Adriana , Hondal Robert , Fischer Matthias , Bartenhagen Christoph , Shimada Briana K. , Seale Lucia A. , Fabiano Marietta , Schweizer Ulrich , Netto Luis E. , Meotti Flavia Carla , Alborzinia Hamed , Miyamoto Sayuri , Friedmann Angeli Jose Pedro
Published: June 2024

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.
CellFM: a large-scale foundation model pre-trained on transcriptomics of 100 million human cells
Authors: Zeng Yuansong , Xie Jiancong , Wei Zhuoyi , Su Yun , Shangguan Ningyuan , Yang Shuangyu , Zhang Chengyang , Li Wenbing , Zhang Jinbo , Fang Nan , Zhang Hongyu , Zhao Huiying , Lu Yutong , Fan Jue , Yu Weijiang , Yang Yuedong
Published: June 2024

The rapid evolution of single-cell sequencing technologies has facilitated precise transcriptomics profiling at the single-cell level, shedding light on the intricate heterogeneity within cellular populations. Despite these advances, the inherent diversity of cells and data challenges such as noise, batch effects, and sparsity, underscores the pressing need for a unified model to learn and represent cellular states effectively. Single-cell Large Language Models (LLMs) have been crafted to bridge this gap yet exhibit limited performance on human cells. This short-fall may stem from the confounding effects of training data from diverse species, partly because of limited cells for the single species. Here, we have compiled a dataset of approximately 100 million human cells sequenced by multiple technolo-gies from human single-cell datasets with various file types deposited in public databases and websites. Leveraging these extensive data cohorts, we developed CellFM, a robust single-cell foundation model with an impressive 800 million parameters, marking an eight-fold increase over the current largest single-species model. To ensure the training of CellFM on the MindSpore AI framework from Huawei, we have integrated RetNet, a Transformer architecture variant with lin-ear complexity for a balance between efficiency and performance, serving as the backbone of our model. Our comprehensive experiments have shown that CellFM outperforms existing models across diverse applications, such as cell annotation, perturbation prediction, and gene function prediction.
Prevention and treatment of noise-induced hearing loss and cochlear synapse degeneration by potassium channel blockersin vivo
Authors: Zhao Hong-Bo , Liu Li-Man , Mei Ling , Quinonez Auraemil T , Roberts Rafael A , Lu Xiaoling
Published: June 2024

Noise can induce hearing loss. In particularly, noise can induce cochlear synapse degeneration leading to hidden hearing loss, which is the most common type of hearing disorders in the clinic. Currently, there is no pharmacological treatment, particularly, no post-exposure (i.e., therapeutic) treatment available in the clinic. Here, we report that systematic administration of K+channel blockers before or after noise exposure could significantly attenuate NIHL and synapse degeneration. After systematic administration of a general K-channel blocker tetraethylammonium (TEA), the elevation of auditory brainstem response (ABR) thresholds after noise-exposure significantly reduced, and the active cochlear mechanics significantly improved. The therapeutic effect was further improved as the post-exposure administration time extending to 3 days. BK channel is a predominant K+channel in the inner hair cells. Systematic administration of a BK channel blocker GAL-021 after noise exposure also ameliorated hearing loss and improved hearing behavioral responses tested by acoustic startle response (ASR). Finally, both TEA and GAL-021 significantly attenuated noise-induced ribbon synapse degeneration. These data demonstrate that K+-channel blockers can prevent and treat NIHL and cochlear synapse degeneration. Our finding may aid in developing therapeutic strategies for post-exposure treatment of NIHL and synapse degeneration.

Significance Statement

Noise is a common deafness factor affecting more 100 million people in the United States. So far, there is no pharmacological treatment available. We show here that administration of K+channel blockers after noise exposure could attenuate noise-induced hearing loss and synapse degeneration, and improved behavioral responses. This is the first time to real the K+channel blockers that could treat noise-induced hearing loss and cochlear synaptopathy after noise exposure.
The Molecular Basis of Differentiation Wave Activity in Embryogenesis
Authors: Alicea Bradly , Bastani Surosh , Gordon Natalie K. , Crawford-Young Susan , Gordon Richard
Published: June 2024

As development varies greatly across the tree of life, it may seem difficult to suggest a model that proposes a single mechanism for understanding collective cell behaviors and the coordination of tissue formation. Here we propose a mechanism called differentiation waves, which unify many disparate results involving developmental systems from across the tree of life. We demonstrate how a relatively simple model of differentiation proceeds not from function-related molecular mechanisms, but from so-called differentiation waves. A phenotypic model of differentiation waves is introduced, and its relation to molecular mechanisms is proposed. These waves contribute to a differentiation tree, which is an alternate way of viewing cell lineage and local action of the molecular factors. We construct a model of differentiation wave-related molecular mechanisms (genome, epigenome, and proteome) based onC. elegansbioinformatic data. To validate this approach across different modes of development, we evaluate protein expression across different types of development by comparing the nematodeCaenorhabditis eleganswith several model organisms: fruit flies (Drosophila melanogaster), yeast (Saccharomyces cerevisiae), and mouse (Mus musculus). Inspired by gene regulatory networks, two Models of Interactive Contributions (fully-connected MICs and ordered MICs) are used to suggest potential genomic contributions to differentiation wave-related proteins. This, in turn, provides a framework for understanding differentiation and development.
Probabilistic graph-based model uncovers previously unseen druggable vulnerabilities in major solid cancers
Authors: Zhu Ying , Schmidt Stephanie T. , Zhao Li , Jiang Chunjie , Micco Patrizio Di , Mitsopoulos Costas , Futreal Andrew , Al-Lazikani Bissan
Published: June 2024

Over half cancer patients lack safe, effective, targeted therapies despite abundant molecular profiling data. Statistically recurrent cancer drivers have provided fertile ground for drug discovery where they exist. But in rare, complex, and heterogeneous cancers, strong driver signals are elusive. Moreover, therapeutically exploitable molecular vulnerabilities extend beyond classical drivers. Here we describe a novel, integrative, generalizable graph-based, cooperativity-led Markov chain model, A3D3a’s MVP (Adaptive AI-Augmented Drug Discovery and Development Molecular Vulnerability Picker), to identify and prioritize key druggable molecular vulnerabilities in cancer. The algorithm exploits cooperativity of weak signals within a cancer molecular network to enhance the signal of true molecular vulnerabilities. We apply A3D3a’s MVP to 19 solid cancer types and demonstrate that it outperforms standard approaches for target hypothesis generation by >3-fold as benchmarked against cell line genetic perturbation and drug screening data. Importantly, we demonstrate its ability to identify non-driver druggable vulnerabilities and highlight 43 novel or emergent druggable targets for these tumors.
Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome
Authors: Chalkley Mary-Bronwen L. , Guerin Lindsey N. , Iyer Tenhir , Mallahan Samantha , Nelson Sydney , Sahin Mustafa , Hodges Emily , Ess Kevin C. , Ihrie Rebecca A.
Published: June 2024

Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in theTSC1orTSC2genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural developmentTSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether such phenotypes are also seen in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopmentin vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss ofTSC2affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
Placental extracellular vesicles from early-onset but not late-onset preeclampsia induce a pro-vasoconstrictive and anti-vasodilatory state in resistance arteries
Authors: Lau Sien Yee , Groom Katie , Hisey Colin L. , Chen Qi , Barrett Carolyn , Chamley Larry
Published: June 2024

Background

The human placenta releases large numbers of extracellular vesicles (EVs) into the maternal circulation throughout pregnancy. In preeclampsia, a hypertensive disorder of pregnancy, the number of EVs increases and the cargo they carry is altered. We investigated whether human placental EVs from pregnancies complicated by preeclampsia directly alter maternal vascular function, a hallmark of the disorder, and if EVs from early-onset or late-onset variants of preeclampsia have different effects on the vasculature.

Methods

Macro-EVs, micro-EVs and nano-EVs were isolated from cultured explants of human placentae from women with early-onset or late-onset preeclampsia, or from normotensive women. EVs were injected intravenously into pregnant mice and either at 30 minutes or 24 hours after injection, the mice were euthanized and the function of second order mesenteric arteries were assessed using wire myography.

Results

Placental EVs from pregnancies with early-onset preeclampsia enhanced vasoconstriction to PE, AngII, and ET-1 whilst impairing vasodilation to ACh and SNP in a time-dependent fashion, most prominently at 24 hours. In contrast, placental EVs from pregnancies with late-onset preeclampsia induced few differences compared to arteries taken from control mice injected with EVs from women with normotensive pregnancies.

Conclusions

To the best of our knowledge, this is the first comparison of vascular function after exposure to the full range of EVs produced by placentae from women with early-onset and late-onset preeclampsia and normotensive women. Placental EVs from early-onset preeclampsia demonstrated the ability to contribute to the development of the high-resistance haemodynamic profiles of women affected by early-onset preeclampsia.
Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity
Authors: Trepka Kai R. , Kidder Wesley A. , Kyaw Than S. , Halsey Taylor , Olson Christine A. , Ortega Edwin F. , Noecker Cecilia , Upadhyay Vaibhav , Stanfield Dalila , Steiding Paige , Guthrie Benjamin G. H. , Spanogiannopoulos Peter , Dumlao Darren , Turnbaugh Jessie A. , Stachler Matthew D. , Van Blarigan Erin L. , Venook Alan P. , Atreya Chloe E. , Turnbaugh Peter J.
Published: June 2024

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derivedex vivocommunities. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of thepreTAoperon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU).preTA+bacteria depleted 5-FU in gut microbiota grownex vivoand the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota,preTA+E. coli, orpreTA-high CRC patient stool. Finally,preTAabundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease.

One Sentence Summary:Gut microbial enzymes can be used to predict and prevent anticancer drug toxicity.