bluuebunny/crossref_metadata_2025 huggingface dataset:
Clostridium aquiflavi sp. nov., isolated from yellow water of Nongxiangxing baijiu in the Yibin region of China
Authors: Sun Sijia , Feng Huifen , Liu Rui , Cheng Jin , Mu Shuaicheng , Liu Yiru , Gao Yi , Yao Su , Zhai Lei
Published: June 2024

A Gram-stain-positive, strictly anaerobic, endospore-forming and rod-shaped (0.6–0.8×2.7–13.1 µm) bacterium, designated as 5 N-1T, was isolated from a yellow water sample collected from the manufacturing process of Nongxiangxing baijiu in the Yibin region of Sichuan, PR China. Growth occurred at 15–40 °C (optimum growth at 37 °C), at pH 6.0–9.0 (optimum growth at pH 7.0) and in NaCl concentrations of 0–1 % (w/v) and ethanol concentrations of 0–2 % (v/v). The major fatty acids in strain 5 N-1T were C16 : 0, C18 : 0 and C14 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, four unidentified aminophospholipids and one unidentified lipid. Phylogenetic analysis of its 16S rRNA gene sequence indicated that strain 5 N-1T was most closely related to Clostridium weizhouense YB-6T (97.70 %) and Clostridium uliginosum DSM 12992T (97.56 %). The average nucleotide identity and digital DNA‒DNA hybridization values between strain 5 N-1T and the above two type strains were 80.89 and 80.05 % and 25.80 and 25.30 %, respectively, which were all below the species thresholds. The genome size of strain 5 N-1T was 3.5 Mbp and the DNA G+C content was 27.5 mol%. Based on the results of phenotypic and genotypic analyses, strain 5 N-1T represents a novel species of the genus Clostridium, for which the name Clostridium aquiflavi sp. nov. is proposed. The type strain is Clostridium aquiflavi 5 N-1T (=CICC 24886T=JCM 35355T).
Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults
Authors: Hawkins Jessie , Idoine Rebecca , Kwon Jun , Shao Andrew , Dunne Elizabeth , Hawkins Elizabeth , Dawson Kayla , Nkrumah-Elie Yasmeen
Published: June 2024

Background

Nicotinamide riboside (NR) is a promising compound for augmenting the intracellular NAD+ pool, potentially mitigating age-related decline and associated conditions. While oral NR supplementation has demonstrated safety and bioavailability in multiple animal and human studies, the effects of intravenous NR (NR IV) are far less understood. Until now, pharmaceutical grade NR was not available for injection research.

Objectives

Given that intravenous administration may offer advantages in certain conditions and contexts, a systematic investigation of the clinical effects of NR IV is warranted.

Methods

The present randomized, double-blinded, placebo-controlled, pilot clinical study was initiated with the primary aim of investigating the safety, tolerability, and the blood NAD+-boosting efficacy of an acute, single dose of NR IV (500 mg, test), NAD+ IV (500 mg, active comparator), oral NR (500 mg, bridge), and saline IV (placebo control) in generally healthy adult participants. The study consisted of two parts; data from 37 and 16 participants in the first and second phases, respectively, were analyzed.

Results

No significant differences in vital signs were detected across groups. In comparison to NAD+ IV, NR IV was associated with fewer and less severe adverse experiences during the infusion; no attributable adverse events were reported through the 14-day follow-up period for any treatment groups. Further, the mean tolerable infusion time for NR IV was 75% less than that of NAD+ IV. No clinically meaningful changes in blood chemistry markers were described in the NR IV condition, whereas an increase in white blood cell counts and neutrophils was observed in the NAD+ IV condition, suggesting the presence of an inflammatory response. Finally, NR IV appeared to promote the most robust increases in NAD+ concentration as measured by dried blood spot analyses, with peak NAD+ levels increasing by 20.7% relative to baseline, and acutely outperforming NAD+ IV (p <0.01) and oral NR (p<0.01) at the 3-hr timepoint.

Conclusion

This is the first study to clinically evaluate NR IV. Overall, acute intravenous infusions of 500 mg NR were safe in the study participants with no attributable adverse events and only minor and transient infusion-related experiences. In comparison to NAD+ IV, NR IV had a faster infusion time with superior tolerability. At 3 hours post-infusion, blood NAD+ levels were significantly higher in the NR IV group compared to the NAD+ IV group. Future studies in larger populations are needed to validate these results.
The mediating role of social network between social trust and life satisfaction of older people: A structural equation model analysis approach
Authors: He Xinyu , Yang Zhaoyong , Li Haimei , Li Shihe , Xu Chuanxin
Published: June 2024

Background

Although studies have demonstrated the relationship between the social trust and life satisfaction of older people, but existing studies have rarely considered the fewer studies have investigated social network as a mediating variable between social trust and life satisfaction.

Methods

In this study, 297 participants (age: ≥60 years) in Chengdu, Sichuan Province, China, completed a questionnaire of social trust, social network, and life satisfaction. Structural equation model analysis and bootstrap methods were used to prove the mediating effect of social network.

Results

Social trust was positively related to life satisfaction (B=0.410; p <0.01) and social network (B=0.472; p <0.01), social network was positively related to life satisfaction (B=0.433; p <0.01). and social network played an intermediary role in the relationship between social trust and life satisfaction (indirect effects = 0.321, bootstrap 95% CI = [0.051, 0.968]).

Conclusion

These findings suggest the importance of social trust for life satisfaction, with social network acting as a positive mediator, particularly in China. In conclusion, this study exploring the mediating effect of social network provides knowledge essential for ensuring a happy old age. The study results can help advance psychological research on life satisfaction of older people and suggest new intervention strategies in this field. We encourage increasing the expansion of social networks through various means to enhance the impact of social trust on life satisfaction of older people.
Identification of distinct and shared biomarker panels in different manifestations of cerebral small vessel disease through proteomic profiling
Authors: Hristovska Ines , Binette Alexa Pichet , Kumar Atul , Gaiteri Chris , Karlsson Linda , Strandberg Olof , Janelidze Shorena , van Westen Danielle , Stomrud Erik , Palmqvist Sebastian , Ossenkoppele Rik , Mattsson-Carlgren Niklas , Vogel Jacob W. , Hansson Oskar
Published: June 2024

The pathophysiology underlying various manifestations of cerebral small vessel disease (cSVD) remains obscure. Using cerebrospinal fluid proximity extension assays and co-expression network analysis of 2,943 proteins, we found common and distinct proteomic signatures between white matter lesions (WML), microbleeds and infarcts measured in 856 living patients, and validated WML-associated proteins in three additional datasets. Proteins indicative of extracellular matrix dysregulation and vascular remodeling, including ELN, POSTN, CCN2 and MMP12 were elevated across all cSVD manifestations, with MMP12 emerging as an early cSVD indicator. cSVD-associated proteins formed a co-abundance network linked to metabolism and enriched in endothelial and arterial smooth muscle cells, showing elevated levels at early disease manifestations. Later disease stages involved changes in microglial proteins, associated with longitudinal WML progression, and changes in neuronal proteins mediating WML-associated cognitive decline. These findings provide an atlas of novel cSVD biomarkers and a promising roadmap for the next generation of cSVD therapeutics.
Extrication of patients trapped following a motor vehicle collision: a systematic scoping review of the literature
Authors: Nutbeam Tim
Published: June 2024

Background

Extrication is the process of removing injured or potentially injured people from their vehicles. The origin of current extrication techniques and paradigms is largely unknown. An understanding of the historical evidence related to motor vehicle collisions (MVCs), injuries and deaths will provide context for accepted, contemporary, extrication practices.

Methods

Extrication related search terms were developed and applied across of range of sources including Clinical and health care data, Trial registries, Grey literature, Academic and specific Transport related sources.

Results

7089 articles were identified, following review, 170 are included in this qualitative synthesis. Key themes / categories included: Extrication training and principles, Injures, Immobilisation, Care during entrapment, Clinical response type, Vehicle deformity intrusion entrapment, and Extrication.

Conclusion

There is a paucity of published evidence to support the current approach to extrication of entrapped patients following an MVC. Focused studies identifying in detail the injures and their sequelae associated with entrapment, the biomechanics of current techniques and ensuring that the patient perspective is captured will enable the development of much needed evidence based multidisciplinary guidance.
Fractal dimension distributions of resting-state EEG improve detection of dementia and Alzheimer's disease compared to traditional fractal analysis
Authors: Yoder Keith J , Brookshire Geoffrey , Glatt Ryan , Merrill David A , Gerrol Spencer , Quirk Colin , Lucero Che
Published: June 2024

Across many resting-state electroencephalography (EEG) studies, dementia is associated with changes to the power spectrum and fractal dimension. Here we describe a novel method to examine changes in fractal dimension over time and within frequency bands. This method, which we call Fractal Dimension Distributions (FDD), combines spectral and complexity information. In this study, we illustrate this new method by applying it to resting-state EEG data recorded from patients with subjective cognitive impairment (SCI) or dementia. We compared the performance of FDD with the performance of standard fractal dimension metrics (Higuchi and Katz FD). FDD revealed larger group differences detectable at greater numbers of EEG recording sites. Moreover, linear models using FDD features had lower AIC and higher R2 than models using standard full time-course measures of fractal dimension. FDD metrics also outperformed the full time-course metrics when comparing SCI with a subset of dementia patients diagnosed with Alzheimer's disease (AD). FDD offers unique information beyond traditional full time-course fractal analyses and may help to identify AD dementia and non-AD dementia.
Local controls modify the effects of timber harvesting on surface soil carbon and nitrogen dynamics
Authors: Ward Elisabeth B. , Ashton Mark S. , Wikle Jessica L. , Duguid Marlyse , Bradford Mark A.
Published: June 2024

Managing for structural complexity to enhance forest ecosystem health and resiliency is increasingly incorporated in silvicultural treatments. High spatial variability in stands managed for structural complexity could obscure the effects of forest management on surface soils. Yet few studies have assessed how within-stand variation in forest structure and other local controls influence surface soil organic matter dynamics over time following timber harvests. We used a stratified random sampling design to capture variation in stand age, legacy structure, soil type, and topography in a second-growth, oak-hardwood forest in the northeastern U.S. We compared surface soil carbon and nitrogen content and availability in 15 harvested stands managed to promote tree regeneration (n= 144 plots) and five unharvested controls (n= 48 plots). We also examined changes over time since harvest in just the harvested stands using a 22-year chronosequence. Forest management strongly influenced surface soil carbon and nitrogen dynamics. The timber harvests had lower soil carbon and nitrogen, microbial biomass, and carbon mineralization but higher nitrogen mineralization. These differences were more pronounced in the drier, less fertile soil type than in more moist, fertile soils. Across the 22-year chronosequence, topography, soil type, and downed woody material density dictated the direction of changes in surface soil carbon and nitrogen over time. Soil carbon and nitrogen accrued over time at drier, higher elevation (∼300 m) sites and under higher densities of fine woody material but declined at lower elevations (∼180 m) and under lower fine woody material. Proximity to legacy trees was associated with higher soil carbon and nitrogen concentrations and availability. Our findings underscore the importance of silvicultural practices that retain structural legacies and downed woody material in shaping surface soil carbon and nitrogen dynamics over time. Our results also highlight how accounting for spatial variation in local controls on soil carbon and nitrogen, such as topography, can improve detection of changes from forest management practices that increase spatial heterogeneity within stands, such as irregular shelterwood and seed tree regeneration methods.
A multi-gene predictive model for the radiation sensitivity of nasopharyngeal carcinoma based on machine learning
Authors: Li Kailai , Liang Junyi , Li Nan , Fang Jianbo , Zhou Xinyi , Zhang Jian , Lin Anqi , Luo Peng , Meng Hui
Published: June 2024

Background

Radiotherapy resistance is a major obstacle to the long-term survival of nasopharyngeal cancer patients, as it is a primary cause of recurrence and metastasis. Identifying radiotherapy-associated biomarkers can help improve the survival prognosis of nasopharyngeal cancer patients. Consequently, discovering biomarkers associated with radiosensitization is crucial.

Methods

We evaluated 113 combinations of machine learning algorithms and ultimately selected 48 to construct a radiotherapy sensitivity score (NPC-RSS) that can predict radiosensitivity in nasopharyngeal cancer patients. Furthermore, we analyzed the relationship between NPC-RSS and the expression of genes associated with immune and radiotherapy sensitivity profiles. We employed GSEA and ssGSEA to investigate the connection between NPC-RSS and signaling pathways.

Results

We selected the combined model glmBoost+NaiveBayes, which had the best AUC among 48 models, for our subsequent study. The NPC-RSS, built based on the 18 genes included in this model, can predict the results of the public dataset and the in-house dataset of Zhujiang Hospital, Southern Medical University, with considerable efficiency. The key genes of NPC-RSS are closely associated with immune characteristics, including chemokine and chemokine receptor families, and histocompatibility complex (MHC), and show more active immune processes. Meanwhile, these key genes were significantly associated with the expression of radiosensitization-related genes. Furthermore, GSVA and GSEA analyses demonstrated that different expression levels of key NPC-RSS genes influenced signaling pathways, such as the Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway,NF-kappa B signaling pathway and T cell receptor signaling pathway, which are associated with immunity and disease progression. The consistency of the expression of key genes SMARCA2 and CD9 with NPC-RSS was validated in in-house cell lines. The radiosensitive group, classified according to NPC-RSS, exhibited a more enriched and activated state of immune infiltration compared to the radioresistant group. Moreover, in single-cell samples, NPC-RSS was higher in the radiotherapy-sensitive group, with immune cells playing a predominant role.

Conclusions

In this study, we used machine learning to construct a predictive score, called NPC-RSS, associated with radiosensitivity in nasopharyngeal carcinoma patients; moreover, NPC-RSS is strongly associated with immune characteristics, expression of radiosensitivity-related genes, and signaling pathways related to disease progression. We hope that the NPC-RCC will enable more precise selection of the NPC population of potential beneficiaries of radiation therapy.
A high-light tolerant alga from the desert is protected from oxidative stress by NPQ-independent responses
Authors: Levin Guy , Yasmin Michael , Liran Oded , Hanna Rawad , Kleifeld Oded , Horev Guy , Wollman Francis-André , Schuster Gadi , Nawrocki Wojciech J.
Published: June 2024

Non-photochemical quenching (NPQ) mechanisms are crucial for protecting photosynthesis from photoinhibition in plants, algae, and cyanobacteria, and their modulation is a long-standing goal for improving photosynthesis and crop yields. The current work demonstrates thatChlorella ohadii, a green micro-alga that thrives in the desert under high light intensities which are fatal to many photosynthetic organisms, does not perform nor require NPQ to protect photosynthesis under constant high light. Instead of dissipating excess energy, it minimizes its uptake by eliminating the photosynthetic antenna of photosystem II. In addition it accumulates antioxidants that neutralize harmful reactive oxygen species (ROS) and ramps up cyclic electron flow around PSI. These NPQ-independent responses proved efficient in preventing ROS accumulation and reducing oxidative damage to proteins in high-light-grown cells.
Mode of action of the toxic proline mimic azetidine 2-carboxylic acid in plants
Authors: Santos William Thives , Dwivedi Varun , Duong Ha Ngoc , Miederhoff Madison , Hoek Kathryn Vanden , Angelovici Ruthie , Schenck Craig A.
Published: June 2024

Plants have an amazing capacity to outcompete neighboring organisms for space and resources. Toxic metabolites are major players in these interactions, which can have a broad range of effectiveness by targeting conserved molecular mechanisms, such as protein biosynthesis. However, lack of knowledge about defensive metabolite pathways, their modes of action, and resistance mechanisms limits our ability to manipulate these pathways for enhanced crop resilience. Nonproteogenic amino acids (NPAAs) are a structurally diverse class of metabolites with a variety of functions but are typically not incorporated during protein biosynthesis. Here, we investigate the mode of action of the NPAA azetidine-2-carboxylic acid (Aze), an analog of the amino acid proline (Pro). Using a combination of plate-based assays, metabolite feeding, metabolomics, and proteomics, we show that Aze inhibits the root growth of Arabidopsis and other plants. Aze-induced growth reduction was restored by supplementing L-, but not D-Pro, and non-targeted proteomics confirms that Aze is misincorporated for Pro during protein biosynthesis, specifically on cytosolically translated proteins. qRT-PCR analysis and free amino acid profiling show that the unfolded protein response is upregulated during Aze treatment implicating protein degradation of misfolded proteins. This study demonstrates the mode of action of Aze in plants and provides a foundation for engineering Aze production and tolerance in crops for enhanced resilience.
Molecular basis of one-step methyl anthranilate biosynthesis in grapes, sweet orange, and maize
Authors: Fallon Michael A. , Tadfie Hisham , Watson Aracely P. , Dyke Madeline M. , Flores Christopher , Cook Nathan , Fei Zhangjun , Holland Cynthia K.
Published: June 2024

Plants synthesize an array of volatile compounds, many of which serve ecological roles in attracting pollinators, deterring herbivores, and communicating with their surroundings. Methyl anthranilate is an anti-herbivory defensive volatile responsible for grape aroma that is emitted by several agriculturally relevant plants, including citrus, grapes, and maize. Unlike maize, which uses a one-step anthranilate methyltransferase, grapes have been thought to use a two-step pathway for methyl anthranilate biosynthesis. By mining available transcriptomics data, we identified two anthranilate methyltransferases inVitis vinifera(wine grape), as well as one ortholog in ‘Concord’ grape. Many angiosperms methylate the plant hormone salicylic acid to produce methyl salicylate, which acts as a plant-to-plant communication molecule. Because theCitrus sinensis(sweet orange) salicylic acid methyltransferase can methylate both anthranilate and salicylic acid, we used this enzyme to examine the molecular basis of anthranilate activity by introducing rational mutations, which identified several active site residues that increase activity with anthranilate. Reversing this approach, we introduced mutations that imparted activity with salicylic acid in the maize anthranilate methyltransferase, which uncovered different active site residues from those in the citrus enzyme. Sequence and phylogenetic analysis revealed that one of theVitisanthranilate methyltransferases shares an ancestor with jasmonic acid methyltransferases, similar to the anthranilate methyltransferase from strawberry (Frageriasp.). Collectively, these data demonstrate the molecular mechanisms underpinning anthranilate activity across methyltransferases and identified one-step enzymes by which grapes synthesize methyl anthranilate.

Significance Statement

While the two-step pathway responsible for the biosynthesis of the grape aroma molecule, methyl anthranilate, has remained incomplete inVitisspp., we identified two one-step anthranilate methyltransferases in wine and one in ‘Concord’ grapes that can methylate the tryptophan pathway intermediate anthranilate. Tracing the molecular basis of anthranilate activity in the maize and sweet orange methyltransferases uncovered distinct active site amino acids that impart substrate specificity.
Long-term maintenance of patient-specific characteristics in tumoroids from six cancer indications in a common base culture media system
Authors: Paul Colin D. , Yankaskas Chris , Shahi Thakuri Pradip , Balhouse Brittany , Salen Shyanne , Bullock Amber , Beam Sylvia , Chatman Anthony , Djikeng Sybelle , Yang Jenny , Wong Garrett , Dey Isha , Holmes Spencer , Dockey Abigail , Bailey-Steinitz Lindsay , Zheng Lina , Li Weizhong , Chandra Vivek , Nguyen Jakhan , Sharp Jason , Willems Erik , Kennedy Mark , Dallas Matt , Kuninger David
Published: June 2024

Tumoroids, also known as cancer organoids, are patient-derived cancer cells grown as 3D, self-organized multicellular structures that maintain key characteristics (e.g., genotype, gene expression levels) of the tumor from which they originated. These models have emerged as valuable tools for studying tumor biology, cytotoxicity, and response of patient-derived cells to cancer therapies. However, the establishment and maintenance of tumoroids has historically been challenging, labor intensive, and highly variable from lab to lab, hindering their widespread use. Here, we characterize the establishment and/or expansion of colorectal, lung, head and neck, breast, pancreas, and endometrial tumoroids using the standardized, serum-free Gibco OncoPro Tumoroid Culture Medium. Newly derived tumoroid lines (n=20) were analyzed by targeted genomic profiling and RNA sequencing and were representative of tumor tissue samples. Tumoroid lines were stable for over 250 days in culture and freeze-thaw competent. Previously established tumoroid lines were also transitioned to OncoPro medium and exhibited, on average, similar growth rates and conserved donor-specific characteristics when compared to original media systems. Additionally, OncoPro medium was compatible with both embedded culture in extracellular matrix and growth in a suspension format for facile culture and scale up. An example application of these models for assessing the cytotoxicity of a natural killer cell line and primary natural killer cells over time and at various doses demonstrated the compatibility of these models with assays used in compound and cell therapy development. We anticipate that the standardization and versatility of this approach will have important benefits for basic cancer research, drug discovery, and personalized medicine and help make tumoroid models more accessible to the cancer research community.
A new locally collected environmental quality indicator for medium and large mammals
Authors: Oliveira Márcio Leite , Gorni Guilherme Rossi , Nascimento Alessandra Santos , Passos Fernando de Camargo
Published: June 2024

Measuring environmental degradation with bioindicators, landscape metrics, and remote sensing helps understand impact on biota. However, data on anthropogenic pressures such as plant exploitation, poaching and invasive species are crucial. We created an Anthropogenic Influence Index (AII) for medium and large mammals at the Atlantic Forest based on local environmental quality indicators and tested its correlation with existing indices, such as the Global Human Influence Index (GHII), landscape metrics and social-economic indicators. We found no correlation between the AII and the GHII, indicating that remote sensing-collected data may not reflect local and specific anthropogenic impacts on the environment. In addition, there was a correlation between the AII and the Human Development Index, drawing attention to the direct relationship between income, education and life expectancy and the incidence of environmental impacts. Thus, the AII appears to better capture local nuances of environmental impacts, particularly those significant for medium and large mammals, compared to other indicators such as GHII, human density, and landscape metrics.
Jagged-1+Tregs Mediate Lymphatic Remodeling in Tumour-Draining Lymph Nodes
Authors: Xu Jessie Z. , Lui Prudence PokWai , Tsai Pei-Hsun , Aziz Hafsah , Xie Boyu , Cho Inchul , Terranova-Barberio Manuela , Li Chao Zheng , Stoker Katie , Yu Hongqiang , Denton Alice E. , Lawrence Toby , Karagiannis Sophia N. , Ali Niwa
Published: June 2024

The tumour-draining lymph nodes (tdLNs) are crucial sites for early immune surveillance of tumours. During tumour development, tdLNs undergo significant stromal remodelling that impacts lymph node (LN) architecture. The reconstruction of tdLNs is dependent on the crosstalk between regulatory T cells (Tregs) and resident stromal cells. The Notch ligand Jagged1 (Jag1), highly expressed in skin Tregs, is critical for facilitating stem cell-mediated tissue regeneration. However, the role of Jag1posTregs in mediating the activity of tdLN-resident immune cells and stromal cells remains unexplored. Here, we used the B16-F10 tumour model to assess the role of Jag1posTregs during tdLN development. During tumor progression, late-stage tdLN Tregs expressed higher levels of Jag1 than early-stage tdLNs. Conditional deletion of Jag1 in Tregs markedly restrained tdLN expansion, without influencing effector T cell abundance or activation profile. Transcriptomic analysis of tdLNs revealed downregulation of lymphatic endothelial cell (LEC)-related markers in mice with Treg-specific Jag1 ablation. Disruption of lymphatic networks in the tdLN was further confirmed by flow cytometric profiling and histological analysis.In vivopermeability assessment by FITC-dextran demonstrated perturbed lymphatic drainage, likely due to suppressed LN lymphangiogenesis. Finally, we identify the presence of Jag1posTregs in tdLNs of human melanoma patients. Overall, our results highlight that crosstalk between Jag1posTregs and LECs is required for lymphatic sinus expansion, which is critical for the formation of the tdLN niche during melanoma progression.
Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface
Authors: Maurice Nicholas J , Erickson Jami R , DeJong Caitlin S , Mair Florian , Taber Alexis K , Frutoso Marie , Islas Laura V , Vigil Anna-Lena BG , Lawler Richard L , McElrath M Juliana , Newell Evan W , Sullivan Lucas B , Shree Raj , McCartney Stephen A
Published: June 2024

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.
MSAGPT: Neural Prompting Protein Structure Prediction via MSA Generative Pre-Training
Authors: Chen Bo , Bei Zhilei , Cheng Xingyi , Li Pan , Tang Jie , Song Le
Published: June 2024

Multiple Sequence Alignment (MSA) plays a pivotal role in unveiling the evolutionary trajectories of protein families. The accuracy of protein structure predictions is often compromised for protein sequences that lack sufficient homologous information to construct high-quality MSA. Although various methods have been proposed to generate virtual MSA under these conditions, they fall short in comprehensively capturing the intricate co-evolutionary patterns within MSA or require guidance from external oracle models. Here we introduce MSAGPT, a novel approach to prompt protein structure predictions via MSA generative pre-training in the low-MSA regime. MSAGPT employs a simple yet effective 2D evolutionary positional encoding scheme to model the complex evolutionary patterns. Endowed by this, its flexible 1D MSA decoding framework facilitates zero-or few-shot learning. More-over, we demonstrate that leveraging the feedback from AlphaFold2 can further enhance the model’s capacity via Rejective Fine-tuning (RFT) and Reinforcement Learning from AF2 Feedback (RLAF). Extensive experiments confirm the efficacy of MSAGPT in generating faithful virtual MSA to enhance the structure prediction accuracy (up to +8.5% TM-Score on few-shot scenarios). The transfer learning capabilities also highlight its great potential for facilitating other protein tasks.
THE HYBRID HISTORY OF ZEBRAFISH
Authors: McCluskey Braedan M. , Batzel Peter , Postlethwait John H.
Published: June 2024

Since the description of the zebrafishDanio rerioin 1822, the identity of its closest living relative has been unclear. To address this problem, we sequenced the exomes of ten species in genusDanioand used them to infer relationships across the 25 chromosomes of the zebrafish genome. The majority of relationships withinDaniowere remarkably consistent across all chromosomes. Relationships of chromosome segments, however, depended systematically upon genomic location within zebrafish chromosomes. Regions near chromosome centers identifiedD. kyathitand/orD. aesculapiias the closest relative of zebrafish, while segments near chromosome ends supported onlyD. aesculapiias the zebrafish sister species. Genome-wide comparisons of derived character states revealed that danio relationships are inconsistent with a simple bifurcating species history and support an ancient hybrid origin of theD. reriolineage. We also found evidence of more recent gene flow limited to the high recombination ends of chromosomes and several megabases of chromosome 20 with a history distinct from the rest of the genome. The additional insight gained from incorporating genome structure into a phylogenomic study demonstrates the utility of such an approach for future studies in other taxa. The multiple genomic histories of species in the genusDaniohave important implications for comparative studies in these species and for our understanding of the hybrid evolutionary history of zebrafish.
Effectiveness of Radiation Therapy for Low- to Intermediate-Grade Neuroendocrine Tumors
Authors: Koenig Julie L. , Carter Justin N. , Aggarwal Sonya , Chang Daniel T. , Loo Billy W. , Diehn Maximilian , Koong Albert C. , Kunz Pamela L. , Gensheimer Michael F.
Published: June 2024

Surgery is the primary treatment for localized neuroendocrine tumors (NETs). Grade 1-2 NETs traditionally have been considered radioresistant due to their indolent nature but data regarding a role for radiation therapy (RT) are limited to old, small retrospective studies. We performed a retrospective review of patients with grade 1-2 NETs treated with RT at a large academic center to assess response and local failure rates. Radiographic response was evaluated with logistic regression. Local failure was assessed with cumulative incidence rates and competing risk regressions. We identified 35 patients with 78 treated lesions between 1974 and 2017. Most tumors originated from the pancreas (n=13) and bronchus/lung (n=11). Nine (26%) patients had grade 1 tumors, 16 (46%) had grade 2 tumors, and ten (29%) had grade 1-2 tumors. The median biologically effective dose (BED10) was 50.7 Gy (range, 20.0-106.5). The median follow-up was 13.5 months (range, 0.5 to 140.6 months). 20 of 21 (95%) patients had palliation of symptoms. Of 52 intact lesions, response was complete in 7 (13%), partial in 14 (27%), stable in 25 (48%), and progressive in 6 (12%) lesions. Higher BED10was associated with a response (odds ratio/Gy 1.06; 95% CI, 1.02-1.11; p=0.008). Of 59 intact or resected lesions, the 2-year cumulative incidence of local failure was 26.4%. Grade 2 lesions were associated with local failure (hazard ratio 7.70; 95% CI, 1.22-48.8; p=0.03). We show that grade 1-2 NETs often respond radiographically and symptomatically to RT. RT should be considered in the management of grade 1-2 NETs.
Is execute attention affected by environmental lighting conditions?
Authors: Wessolowski Nino , Rahim Raschida Jasmin
Published: June 2024

Bright daylight has various positive influences, such as the long-term synchronization of circadian rhythms and an associated alertness that creates optimal conditions for attentional performance. However, the short-term effects of light on attention have not yet been sufficiently researched. Studies of these short-term effects on selective attention also showed partly contradictory effects. To investigate these short-term effects, 95 participants completed the Attention Network Test, under conditions of bright daylight or warm-white light. The focus of the present study was on executive attention, because this construct comes closest to the ANT short form of selective attention used. A significant enhancement of executive attention was observed under bright daylight conditions. This specifically means a short term effect of bright daylight on executive attention and thus selective attention in young adults.
Assessing the Role of Patient Generation Techniques in Virtual Clinical Trial Outcomes
Authors: Gevertz Jana L. , Wares Joanna R.
Published: June 2024

Virtual clinical trials (VCTs) are growing in popularity as a tool for quantitatively predicting heterogeneous treatment responses across a population. In the context of a VCT, a plausible patient is an instance of a mathematical model with parameter (or attribute) values chosen to reflect features of the disease and response to treatment for that particular patient. A number of techniques have been introduced to determine the set of model parametrizations to include in a virtual patient cohort. These methodologies generally start with a prior distribution for each model parameter and utilize some criteria to determine whether a parameter set sampled from the priors should be included or excluded from the plausible population. No standard technique exists, however, for generating these prior distributions and choosing the inclusion/exclusion criteria. In this work, we rigorously quantify the impact that VCT design choices have on VCT predictions. Rather than use real data and a complex mathematical model, a spatial model of radiotherapy is used to generate simulated patient data and the mathematical model used to describe the patient data is a two-parameter ordinary differential equations model. This controlled setup allows us to isolate the impact of both the prior distribution and the inclusion/exclusion criteria on both the heterogeneity of plausible populations and on predicted treatment response. We find that the prior distribution, rather than the inclusion/exclusion criteria, has a larger impact on the heterogeneity of the plausible population. Yet, the percent of treatment responders in the plausible population was more sensitive to the inclusion/exclusion criteria utilized. This foundational understanding of the role of virtual clinical trial design should help inform the development of future VCTs that use more complex models and real data.
Interactive Learning with ChatGPT: Hands-On Practice and Real-Time Feedback in Health Sciences Education for SMART Goal Writing
Authors: Speer Julie E. , Parker Sara M. , Williams Brittany L.
Published: June 2024

Physical therapy (PT) students often fail to master documentation skills, such as goal writing, because they struggle to engage in the material early in the curriculum. Therefore, we sought to leverage ChatGPT to create an active learning experience with personalized feedback and hands-on practice. During the activity, students (n=48) learned to use ChatGPT and employed these techniques to learn about goal writing in PT and the SMART (Specific, Measurable, Attainable, Relevant, Time-bound) framework. Next, students engaged in a clarifying lecture before using ChatGPT to generate scenarios for which they drafted or edited SMART goals and asked ChatGPT for feedback. Pre-tests and post-tests were used to measure the impacts of the experience and to capture student perspectives. As a function of the activity, students were better able to recognize the purposes of SMART goals (p<0.0001) and write better goals (p<0.0001). They also showed increased confidence in their abilities (p<0.0001). Furthermore, student responses suggested that they enjoyed the activity (m=3.5/4) and found it helpful (m=3.7/4). Following the activity, 27 students continued to use ChatGPT to practice or study. This activity represents a novel approach for using generative artificial intelligence (AI) in the classroom to help students actively explore the topic of goal writing. Additionally, this modeled responsible use of AI for health care applications. This well-received activity can be easily scaled to include more complex tasks or group discussions, or adapted for use as an asynchronous assignment related to documentation or topics across health science education.
State-level disparities in cervical cancer prevention and outcomes in the U.S.: A modeling study
Authors: Alarid-Escudero Fernando , Gracia Valeria , Wolf Marina , Zhao Ran , Easterly Caleb W. , Kim Jane J. , Canfell Karen , de Kok Inge M.C.M. , Barnabas Ruanne V. , Kulasingam Shalini
Published: June 2024

Background

Despite HPV vaccines’ availability for over a decade, coverage across the US varies. While some states have tried to increase HPV vaccination coverage, most model-based analyses focus on national impacts. We evaluated hypothetical changes in HPV vaccination coverage at the national and state levels for California, New York, and Texas using a mathematical model.

Methods

We developed a new mathematical model of HPV transmission and cervical cancer, creating US and state-level models, incorporating country- and state-specific vaccination coverage and cervical cancer incidence and mortality. We quantified the national and state-level impact of increasing HPV vaccination coverage to 80% by 2025 or 2030 on cervical cancer outcomes and the time to elimination defined as <4 per 100k women.

Results

Increasing vaccination coverage to 80% in Texas over ten years could reduce cervical cancer incidence by 50.9% (95% credible interval [CrI]:46.6-56.1%) by 2100, from 1.58 (CrI:1.19-2.09) to 0.78 (CrI:0.57-1.02) per 100,000 women. Similarly, New York could see a 27.3% (CrI:23.9-31.5%) reduction, from 1.43 (CrI:0.93-2.07) to 1.04 (Crl:0.66-1.53) per 100,000 women, and California a 24.4% (CrI:20.0-30.0%) reduction, from 1.01 (Crl:0.66-1.44) to 0.76 (Crl:0.50-1.09) per 100,000 women. Achieving 80% coverage in five years will provide slightly larger and sooner reductions. If the vaccination coverage levels in 2019 continue, cervical cancer elimination could occur nationally by 2051 (Crl:2034-2064), but state timelines may vary by decades.

Conclusion

Targeting an HPV vaccination coverage of 80% by 2030 will disproportionately benefit states with low coverage and higher cervical cancer incidence. Geographically focused analyses can better inform priorities.
Sex-differences in Newly Diagnosed Severe Aortic Stenosis in British Columbia (B.C.) between 2012 - 2022
Authors: Roshan Aishwarya , Yim Jeffrey , Lakhani Shamikh , Wang Jennifer , Sidhu Aamiya , Sayre Eric C. , Humphries Karin , Sathananthan Janarthanan , Wood David , Tsang Michael Y.C. , Yeung Darwin F. , Luong Christina , Nair Parvathy , Gin Kenneth , Jue John , Webb John G. , Tsang Teresa S.M.
Published: June 2024

Background

Despite its high prevalence, little is known about the effect of sex on the management and outcomes of aortic stenosis (AS). We sought to characterize the effect of sex on the clinical evaluation for and provision of aortic valve replacement (AVR), including surgical (SAVR) and transcatheter aortic valve replacement (TAVR), and subsequent morbidity and mortality outcomes.

Methods

A comprehensive chart review was conducted on all patients with a first diagnosis of severe aortic stenosis (AS) at Vancouver General and University of British Columbia Hospitals from 2012 to 2022. Exact chi-square and Kruskal-Wallis tests were used to evaluate variables of interest.

Results

A total of 1794 studies met inclusion criteria, comprising 782 females (44%) and 1012 males (56%). Females were significantly older than males at the time of first diagnosis (79 versus 75 years, p<0.001). Females were significantly less likely to be evaluated by the TAVR clinic, cardiac surgeon, or to receive aortic valve intervention (p-value≤0.001).

Females were significantly more likely to be rejected for TAVR due to older age (OR 0.23 (0.07, 0.59)), comorbid conditions (OR 0.68 (0.47, 0.97)), and frailty (OR 0.23 (0.07, 0.59)). Females were significantly more likely to be rejected for SAVR on the basis of frailty (OR 0.66 (0.46, 0.94)). Females also had significantly higher rates of 1-year mortality, hospitalization, and heart failure hospitalization compared to males (p-values < 0.05).

Conclusion

Our data suggest significant sex-based discrepancies in the management of AS. Females with severe AS are diagnosed later in life and are less likely to be evaluated for valve intervention. They are less likely to receive intervention due to older age, frailty, and multimorbid conditions. Further research is warranted for more effective identification and follow up of aortic stenosis as well as timely referral for AVR, where appropriate, especially of females.
Stroke Risk Reduction in Migraine Patients Using Propranolol: Evidence from Two Large-Scale Real-World Data Analyses
Authors: Jeong Eugene , Mogos Mulubrhan F. , Chen You
Published: June 2024

Background:

Propranolol, a non-selective beta-blocker, is commonly used for migraine prevention, but its impact on stroke risk among migraine patients remains controversial. Using two large electronic health records-based datasets, we examined stroke risk differences between migraine patients with- and without- documented use of propranolol

Methods:

This retrospective case-control study utilized EHR data from the Vanderbilt University Medical Center (VUMC) and the All of Us Research Program. Migraine patients were first identified based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria using diagnosis codes. Among these patients, cases were defined as those with a primary diagnosis of stroke following the first diagnosis of migraine, while controls had no stroke after their first migraine diagnosis. Logistic regression models, adjusted for potential factors associated with stroke risk, assessed the association between propranolol use and stroke risk, stratified by sex and migraine subtype. A Cox proportional hazards regression model was used to estimate the hazard ratio (HR) for stroke risk at 1, 2, 5, and 10 years from baseline.

Results:

In the VUMC database, 378 cases and 15,209 controls were identified, while the All of Us database included 267 cases and 6,579 controls. Propranolol significantly reduced stroke risk in female migraine patients (VUMC: OR=0.52, p=0.006; All of Us: OR=0.39,p=0.007), but not in males. The effect was more pronounced for ischemic stroke and in females with migraines without aura (MO) (VUMC: OR=0.60, p=0.014; All of Us: OR=0.28, p=0.006). The Cox model showed lower stroke rates in propranolol-treated female migraine patients at 1, 2, 5, and 10 years (VUMC: HR=0.06-0.55, p=0.0018-0.085; All of Us: HR=0.23, p=0.045 at 10 years).

Conclusions:

Propranolol is associated with a significant reduction in stroke risk, particularly ischemic stroke, among female migraine without aura patients. These findings suggest that propranolol may benefit stroke prevention in high-risk populations.