bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering Rubisco Condensation in Chloroplasts to Manipulate Plant Photosynthesis
Authors: Chen Taiyu , Hojka Marta , Davey Philip , Sun Yaqi , Zhou Fei , Lawson Tracy , Nixon Peter J. , Lin Yongjun , Liu Lu-Ning
Published: September 2024

Although Rubisco is the most abundant enzyme globally, it is inefficient for carbon fixation because of its low turnover rate and limited ability to distinguish CO2and O2, especially under high O2conditions. To address these limitations, phytoplankton, including cyanobacteria and algae, have evolved CO2-concentrating mechanisms (CCM) that involve compartmentalizing Rubisco within specific structures, such as carboxysomes in cyanobacteria or pyrenoids in algae. Engineering plant chloroplasts to establish similar structures for compartmentalizing Rubisco has attracted increasing interest for improving photosynthesis and carbon assimilation in crop plants. Here, we present a method to effectively induce the condensation of endogenous Rubisco within tobacco (Nicotiana tabacum) chloroplasts by genetically fusing superfolder green fluorescent protein (sfGFP) to the tobacco Rubisco large subunit (RbcL). By leveraging the intrinsic oligomerization feature of sfGFP, we successfully created pyrenoid-like Rubisco condensates that display dynamic, liquid-like properties within chloroplasts without affecting Rubisco assembly and catalytic function. The transgenic tobacco plants demonstrated comparable autotrophic growth rates and full life cycles in ambient air relative to the wild-type plants. Our study offers a promising strategy for modulating endogenous Rubisco assembly and spatial organization in plant chloroplasts via phase separation, which provides the foundation for generating synthetic organelle-like structures for carbon fixation, such as carboxysomes and pyrenoids, to optimize photosynthetic efficiency.
Causal associations between plasma proteins and prostate cancer: a Proteome-Wide Mendelian Randomization
Authors: Lin Chen , Zhuona Rong , Yanlun Gu , Yuke Chen , Wei Yu , Ying Zhou , Xiaocong Pang
Published: September 2024

Background

Due to the limitations in specificity of current diagnostic methods for prostate cancer (PCa), more reliable biomarkers are needed to explore for improving early detection. Plasma proteins represent a promising source of biomarkers, therefore understanding the causal relationships between specific plasma proteins and PCa could be conductive to identify novel biomarkers and therapeutic targets for PCa prevention and treatment.

Methods

We performed a meta-analysis of two independent genome-wide association studies (GWASs) including 94,397 individuals with PCa and 192,372 controls. A mendelian randomization (MR) supplemented by colocalization analysis was conducted, usingcis-acting variants on 4,907 plasma proteins from deCODE Genetics (N=35,559) and 2,940 plasma proteins from UK Biobank Pharma Proteomics Project (UKB-PPP) (N=54,219). Then, the biological pathway analysis and druggability evaluation of the risk proteins were further performed.

Results

Five possible susceptibility loci (JAZF1, PDILM5, WDPCP, EEFSEC, and TNS3) for PCa were identified through the meta-analysis of GWASs. Among 3,722 plasma proteins, 193 proteins were associated with PCa risk, of which 20 high-risk proteins, including KLK3, were validated in both the deCODE and UKB-PPP cohorts. Functional annotation of these genes encoding proteins confirmed enrichment of immune response, inflammatory response, cell-cell interaction and so on. Genetic colocalization and druggable genome analyses also identified several potential drug targets for PCa, such as HSPB1, RRM2B and PSCA.

Conclusions

We identified novel variants as well as several protein biomarkers linked to PCa risk and indicated pathways associated with PCa, which offered new insights into PCa etiology and contributed to development of novel biomarkers for early detection and potential therapeutic interventions.

Funding

This work was supported by grants from Beijing Municipal Natural Science Foundation (grant No. JQ24059, No. L234038) and National Natural Science Foundation of China (grant No. 82274015).

Graphical abstract

A comprehensive study design summarized as follows.

Abstract Figure
Multi-gesture drag-and-drop decoding in a 2D iBCI control task
Authors: Gusman Jacob T. , Hosman Tommy , Crawford Rekha , Singer-Clark Tyler , Kapitonava Anastasia , Kelemen Jessica N. , Hahn Nick , Henderson Jaimie M. , Hochberg Leigh R. , Simeral John D. , Vargas-Irwin Carlos E.
Published: September 2024

Objective

Intracortical brain-computer interfaces (iBCIs) have demonstrated the ability to enable point and click as well as reach and grasp control for people with tetraplegia. However, few studies have investigated iBCIs during long-duration discrete movements that would enable common computer interactions such as “click-and-hold” or “drag-and-drop”.

Approach

Here, we examined the performance of multi-class and binary (attempt/no-attempt) classification of neural activity in the left precentral gyrus of two BrainGate2 clinical trial participants performing hand gestures for 1, 2, and 4 seconds in duration. We then designed a novel “latch decoder” that utilizes parallel multi-class and binary decoding processes and evaluated its performance on data from isolated sustained gesture attempts and a multi-gesture drag-and-drop task.

Main Results

Neural activity during sustained gestures revealed a marked decrease in the discriminability of hand gestures sustained beyond 1 second. Compared to standard direct decoding methods, the Latch decoder demonstrated substantial improvement in decoding accuracy for gestures performed independently or in conjunction with simultaneous 2D cursor control

Significance

This work highlights the unique neurophysiologic response patterns of sustained gesture attempts in human motor cortex and demonstrates a promising decoding approach that could enable individuals with tetraplegia to intuitively control a wider range of consumer electronics using an iBCI.
Dynamic MR of muscle contraction during electrical muscle stimulation as a potential diagnostic tool for neuromuscular disease
Authors: Santini Francesco , Croce Michele Giovanni , Deligianni Xeni , Paoletti Matteo , Barzaghi Leonardo , Bergsland Niels , Faggioli Arianna , Manco Giulia , Bonizzoni Chiara , Jin Ning , Ravaglia Sabrina , Pichiecchio Anna
Published: September 2024

Thanks to the rapid evolution of therapeutic strategies for muscular and neuromuscular diseases, the identification of quantitative biomarkers for disease identification and monitoring has become crucial. Magnetic resonance imaging (MRI) has been playing an important role by noninvasively assessing structural and functional muscular changes. This exploratory study investigated the potential of dynamic MRI during neuromuscular electrical stimulation (NMES) to detect differences between healthy controls (HCs) and patients with metabolic and myotonic myopathies. The study included 14 HCs and 10 patients with confirmed muscular diseases. All individuals were scanned with 3T MRI with a protocol that included a multi-echo gradient echo sequence for fat fraction quantification, multi-echo spin-echo for water T2 relaxation time calculation, and 3D phase contrast sequences during NMES. The strain tensor, buildup and release rates were calculated from velocity datasets. Results showed that strain and strain buildup rate were reduced in the soleus muscle of patients compared to HCs, suggesting these parameters could serve as biomarkers of muscle dysfunction. Notably, there were no significant differences in fat fraction or water T2 measurements between patients and HCs, indicating that the observed changes reflect alterations in muscle contractile properties that are not reflected by structural changes. The findings provide preliminary evidence that dynamic muscle MRI during NMES can detect abnormalities in muscle contraction in patients with myotonia and metabolic myopathies, warranting further research with larger, more homogeneous patient cohorts.
Partial dependence of ultrasonically estimated fetal weight on biometric parameters
Authors: Bitsouni Vasiliki , Gialelis Nikolaos , Tsilidis Vasilis
Published: September 2024

Objectives

To assess the contribution of each sonographically measured parameter on fetal weight formulas.

Methods

Multiple datasets and datasets extracted from existing literature are employed in this study. The Sobol’ method is then implemented on each of these datasets. Following this, bootstrapping is carried out using the indices from individual weeks as sample points. The mean value for each resulting sample is calculated. Finally, the median, along with a 95% confidence interval, is estimated based on the empirical distribution. This methodology is repeated for all formulas examined.

Results

The median, along with a 95% CI, for the estimate of the mean of the Sobol’ sensitivity indices for the parameters of 29 known formulas are presented.

Conclusions

Depending on the formula, the values of some parameters show substantial fluctuations or are insignificant to the fetal weight estimation.
Who are the Speech-Language Pathologists of the Future? Results of a national demographic survey of Canadian SLP Students
Authors: Wood Emily , Kika Mariya , Molnar Monika
Published: September 2024

Speech-language pathologists (SLPs) are experts in communication and swallowing who work with individuals across the lifespan. Prior demographic surveys in English-speaking countries (e.g., Canada and the United States) suggest that SLPs’ gender, racial, linguistic, and cultural and socioeconomic backgrounds may not be aligned with those of their clientele. The aim of this study is to describe the demographic characteristics of current SLP students, to gauge whether the demographic composition of future clinicians is changing and is aligned with the population they are trained to serve. We designed an anonymous online survey, in the Canadian context, that enabled us to compare current SLP student demographics with statistics available about the target population at large. This survey was disseminated to all SLP students enrolled in an accredited institution in 2024. Participants answered questions about their age, sex and gender, linguistic, racial and cultural identities, and socioeconomic status. More than half (N=525, 53%) of currently enrolled SLP students completed the survey. Results indicate that SLP students are overwhelmingly cisgender females. SLP students spoke 48 unique languages, and while most were bi or multilingual, few felt competent enough in languages other than English and French to engage in clinical service delivery. There were 151 unique racial and ethnic identities reported, with the largest proportion of students identifying as “North American.” Culturally most SLPs identified as “Canadian.” Very few students identified as Black or Indigenous racially or culturally. Most respondents reported a higher-than-average total household income. Findings suggest that the demographic composition of current SLP students is more diverse than those currently practicing, however there is still over-, and underrepresentation of certain populations. Implications for practice and suggestions for future research are discussed.
Evaluating Observer Reliability and Diagnostic Accuracy of CT-LEFAT Criteria for Post-Treatment Head and Neck Lymphedema: A Prospective Blinded Comparative Analysis of Oncologist Human Inter-Rater Performance
Authors:   MD Anderson Head and Neck Cancer Symptom Working Group, West Natalie A. , Attia Serageldin K. , Kaffey Zaphanlene , Dede Cem , Mulder Samuel L. , El-Habashy Dina M. , Neuberger Roger , Naser Mohamed A. , Frank Steven J. , Mao Shitong , McMillan Holly , Smith Brad , Rosenthal David , Lai Stephen Y. , Hutcheson Katherine A. , Moreno Amy C. , Fuller Clifton D.
Published: September 2024

Background

Radiation-associated lymphedema and fibrosis (LEF) is a significant toxicity following radiation therapy (RT) for head and neck cancer (HNC) patients. Recently, the CT Lymphedema and Fibrosis Assessment Tool (CT-LEFAT) was developed to standardize LEF diagnosis through fat stranding visualized on CT. This study aims to evaluate the inter-observer reliability and diagnostic accuracy of the CT-LEFAT criteria.

Materials and Methods

This study retrospectively evaluated 26 HNC patients treated with RT that received a minimum of two contrast-enhanced CT scans. Qualitative review was conducted by five physician raters to assess the fat stranding observed on CT according to the CT-LEFAT criteria. Fleiss’ kappa analysis was used to assess the inter- and intra-rater reliability, and Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) analysis was used to evaluate diagnostic accuracy.

Results

The inter-rater reliability across the six CT-LEFAT regions generally indicated a slight to fair agreement across all raters (0.04 ≤ kappa ≤ 0.36). Intra-observer agreement was generally fair to moderate (overall kappa=0.44). The ROC AUC analysis varied based on aggregation method used (0.60 ≤ average AUC ≤ 0.70).

Conclusion

This specific use-case evaluating CT-LEFAT criteria displays limited performance. This suggests that additional materials, such as further training, refinement of imaging methods, or other processes may be required before achieving clinically-ready diagnostic performance of LEF diagnosis.
“WE CAN ALL CONTRIBUTE IN OUR OWN WAY”: KNOWLEDGE MOBILIZATION TOOLS TO PROMOTE BEST PRACTICES IN UNIVERSAL ACCESSIBILITY
Authors: Corcuff Maëlle , Routhier François , Lamontagne Marie-Eve
Published: September 2024

Background

Cities aim to enhance urban accessibility following the adoption of the United Nations’ Convention on the Rights of Persons with Disabilities. However, implementation faces challenges due to complex municipal legislation, lack of awareness, and organizational obstacles. Engaging stakeholders and empowering municipal employees through knowledge mobilization is crucial, as shown in a Quebec City’s partnership research process.

Aim

To report the implementation strategy as implemented, explore the perception of the employees about the format and feasibility of the implementation strategy and explore the induced changes of knowledge mobilization tools on the implementation determinants of universal accessibility measures for municipal employees.

Methods

The study used a multi-method design, involving interviews and a questionnaire with the project steering committee, made up of city employees and the research team. Three 30-minute participatory workshops were conducted for culture, communications, and public consultation administrative units.

Results

Participants appreciated the workshop format and video content, suggesting minor improvements for broader implementation. The tools effectively increased engagement in implementing universal accessibility measures, proving valuable for raising awareness.

Discussion and Conclusion

The study demonstrates the advantages of a collaborative approach in developing knowledge mobilization tools, enhancing municipal personnel’s capacity for universal accessibility measures, and highlighting the need for adaptable strategies.

Contributions to the litterature

Knowledge mobilization tools created in partnership with knowledge users encourage buy-in and a positive view of the tools.

An interactive implementation strategy actively involving knowledge users promotes awareness and behavior change

Municipal organizations’ context being complex, the implementation strategy must be adapted to each group of people and their reality to facilitate the implementation and adoption of the tools.

The combined use of a theoretical framework and a participatory approach provides a guideline for the development of tools and implementation, while adapting to the specific context.
National trends in drug overdose mortality in Asian American, Native Hawaiian, and Pacific Islander populations, 2018-2022
Authors: Zhu David T. , Park Andrew
Published: September 2024

Background

Drug overdose deaths have surged over the past two decades, disproportionately impacting racial/ethnic minority populations. Yet, little is known about drug overdose patterns among Asian American and Native Hawaiian/Pacific Islander (AANHPI) populations.

Methods

We obtained data on drug overdose deaths and population totals from the CDC WONDER Multiple Cause of Death database and American Community Survey between 2018 and 2022. We calculated crude mortality rates per 100,000, stratified by sex, US Census Division, and drug types—prescription opioids, heroin, fentanyl, cocaine, methamphetamine, and benzodiazepines. Additionally, we conducted disaggregated analyses for six Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) and three NHPI subgroups (Hawaiian, Guamanian, Samoan).

Results

In 2022, there were 1226 drug overdose deaths among Asian Americans and 154 among NHPI individuals. The crude mortality rate for NHPI individuals (17.52 per 100,000; 95% CI: 14.76– 20.29) tripled that of Asian Americans (5.85 per 100,000; 95% CI: 5.52–6.18). Fentanyl was the leading cause of overdose deaths among Asian Americans (3.17 per 100,000; 95% CI: 2.93– 3.41), whereas methamphetamine was predominant among NHPI individuals (11.38 per 100,000; 95% CI: 9.15–13.61). Among Asian American subgroups, Japanese Americans had the highest mortality rate (9.90 per 100,000; 95% CI: 9.61–10.2), and among NHPI subgroups, Guamanians had the highest rates (43.16 per 100,000; 95% CI: 39.05–48.24).

Conclusions

These findings underscore the urgent need for culturally competent harm reduction services, mental health and addiction treatment, and social services, addressing structural barriers that perpetuate drug overdose disparities in AANHPI communities.
Causes of Pediatric Deaths in Lusaka, Zambia: A Quantitative Geographic Information Systems Approach
Authors: Sportiello Kristen , Shah Mina , Buda Alexandra , Mwanza Isaiah , Mathews Manoj , Bearden David R.
Published: September 2024

Background

While childhood mortality has been declining in Zambia, it remains high at 58 per 1000 live births. Importantly, many leading causes of mortality in Zambia are preventable. This study was conducted to identify clusters of childhood mortality, causes of death of recently deceased children, barriers to care, and risk factors for mortality in Lusaka, Zambia.

Methods

This study was conducted as a prospective cohort study. Family members or lawfully authorized representatives (LARs) were interviewed when they came to pick up death certificates for recently deceased children from Lusaka Children’s Hospital. Each interview included a verbal autopsy, determination of the child’s location of residence, and collection of demographic information. Demographic data was also collected from a healthy control group. Quantitative Geographic Information Systems was used to visualize mortality and evaluate for clustering.

Results

Leading primary causes of death included malnutrition (21%), complications of chronic illnesses (16%), and central nervous system infections (13%), while the leading barriers to care were cost (58%) and difficulties with travel (53%). Compared to controls, recently deceased children came from families with significantly lower incomes (1905 Kwacha vs. 2412 Kwacha, p = 0.03) and were significantly more likely to have a history of malnutrition (16.7% vs. 1.4%, p = 0.005). Mortality was clustered in two high-population density, low-income neighborhoods in Lusaka.

Conclusions

Systems to reduce financial barriers to care and improve access to transportation could reduce childhood mortality in Lusaka. The aforementioned neighborhoods are ideal locations for public health interventions or improved healthcare services.
Adherence, Adverse Events and Viral Control among Children and Adolescents with HIV in Zambia Switched to an Integrase Inhibitor Regimen
Authors: Bearden David R. , Sportiello Kristen , Mweemba Milimo , Lungu Frank , Mwanza-Kabaghe Sylvia , Birbeck Gretchen
Published: September 2024

Background

Based on recent World Health Organization recommendations, there has been a large-scale transition in Sub-Saharan Africa to integrase inhibitor (II)-based antiretroviral therapy (ART) regimens.

Setting

This study was conducted at an urban referral center in Lusaka, Zambia.

Methods

This study included 297 children and adolescents with HIV (CAWH) on ART for one year prior to enrollment and followed for 1-4 years after enrollment. ART adherence, ART regimen, and viral load were assessed periodically. Structured interviews were conducted with a subset of 95 children to assess adherence barriers and side effects.

Results

Children on protease inhibitor (PI)-based regimens were more likely to report adherence problems than children taking II- or Efavirenz-based regimens (10% vs. 28%, p=0.03) and noted more days with missed doses (median 1 vs. 0, p=0.02). In interviews, the most common reasons given for poor adherence included bad medication taste, not being home when medications were due, and perceived side effects. The PI group was more likely to report that taste was a problem affecting adherence (22% vs. 4%, p=0.05) and headache as an ART side effect (17% vs. 4%, p=0.05). Switching from a PI- to an II-based regimen was associated with improved adherence (72% vs. 92%, p=0.01) and an undetectable viral load (67% vs. 78%).

Conclusions

Switching CAWH from PI-based to II-based regimens has many advantages including superior side effect profiles, adherence, and viral suppression. PI taste aversion may be a significant contributor to pediatric adherence issues. Palatability should be considered in pediatric HIV drug development.
WITHDRAWN: A Qualitative Study of User Experiences in Harm Reduction Programs
Authors: Adebayo Olasehinde Ben , Innis Teresa
Published: September 2024

Withdrawal Statement

This manuscript has been withdrawn following a formal request from the Research Ethics Office of the University of Saskatchewan.
Where Adults with Heart Failure Die: Insights from the CDC-WONDER Database
Authors: Ali Farman , Ahmad Shaaf , Ullah Aman , Raja Adarsh , Ahmed Faizan , Perswani Prinka , Alam Ahsan , Mattampuram Jishanth , Maniya Talha , Janjua Hamza , Bonkowski Tyler J. , Nanjundappa Aravinda
Published: September 2024

ABSTRACT

BACKGROUND

Heart failure (HF) is associated with high mortality rates and substantial healthcare costs. Although there is increasing emphasis on introducing palliative care for patients with HF, it is not well characterized where adults with HF spend their final days before death.

STUDY AIM

This study analyzed the locations and circumstances of death among adults with HF in the United States using data from the CDC-WONDER database.

METHODOLOGY

The study examined mortality data of individuals aged ≥ 20 years, with HF listed as the underlying cause of death between 1999 and 2023. The place of death was categorized as the emergency room (ER), hospice/nursing home, inpatient medical facility, or home. Multivariable logistic regression was used to determine the relationship between death location and demographic factors.

RESULTS

From 1999 to 2023, HF-related deaths decreased from 1999 (3.60% and 143.6 AAMR) to 2010 (3.47% and 123.1 AAMR). From 2010 onwards, a gradual rise is seen, with the rate of HF deaths reaching 5.18% and 168.1 AAMR in 2023. Notably, deaths at home increased from 18.41% (50,648 of 275,132) in 1999 to 33.47% (132,470 of 395,826) in 2023 and deaths in hospice/nursing homes increased from 30.95% (85,144 of 275,132) in 1999 to 34.71% (116,634 of 336,014) in 2017 and then sudden fall was observed until 2023 to 29.54% (116,931 of 395,826). Older adults (65+) were more likely to die in inpatient facilities. Gender, ethnicity, and urbanization influenced the place of death, with males, White patients, and those residing in large metropolitan areas more likely to die in medical facilities.

CONCLUSIONS

This study highlights the changing patterns in the locations of death among HF patients, emphasizing the need for improved home and hospice care services. Addressing disparities in healthcare access and enhancing palliative care are essential for improving end-of-life experiences. Further research is needed to investigate the factors that contribute to these trends.
Beyond the Spectrum: Subtype-Specific Molecular Insights into Autism Spectrum Disorder Via Multimodal Data Integration
Authors: Zahiri Javad , Mirzaie Mehdi , Duan Kuaikuai , Xiao Yaqiong , Aamodt Caitlin , Yang Xiaotong , Nazari Sanaz , Andreason Charlene , Lopez Linda , Barnes Cynthia Carter , Arias Steven , Nalabolu Srinivasa , Garmire Lana , Wang Tianyun , Hoekzema Kendra , Eichler Evan E. , Pierce Karen , Lewis Nathan E. , Courchesne Eric
Published: September 2024

Some toddlers with autism spectrum disorder (ASD) have mild social symptoms and developmental improvement in skills, but for others, symptoms and abilities are moderately or even severely affected. Those with profound autism have the most severe social, language, and cognitive symptoms and are at the greatest risk of having a poor developmental outcome. The little that is known about the underlying biology of this important profound autism subtype, points clearly to embryonic dysregulation of proliferation, differentiation and neurogenesis. Because it is essential to gain foundational knowledge of the molecular biology associated with profound, moderate, and mild autism clinical subtypes, we used well-validated, data-driven patient subtyping methods to integrate clinical and molecular data at 1 to 3 years of age in a cohort of 363 ASD and controls representative of the general pediatric population in San Diego County. Clinical data were diagnostic, language, cognitive and adaptive ability scores. Molecular measures were 50 MSigDB Hallmark gene pathway activity scores derived from RNAseq gene expression. Subtyping identified four ASD, typical and mixed diagnostic clusters. 93% of subjects in one cluster were profound autism and 93% in a different cluster were control toddlers; a third cluster was 76% moderate ability ASD; and the last cluster was a mix of mild ASD and control toddlers. Among the four clusters, the profound autism subtype had the most severe social symptoms, language, cognitive, adaptive, social attention eye tracking, social fMRI activation, and age-related decline in abilities, while mild autism toddlers mixed within typical and delayed clusters had mild social symptoms, and neurotypical language, cognitive and adaptive scores that improved with age compared with profound and moderate autism toddlers in other clusters. In profound autism, 7 subtype-specificdysregulated gene pathways were found; they control embryonic proliferation, differentiation, neurogenesis, and DNA repair. To find subtype-commondysregulated pathways, we compared all ASD vs TD and found 17 ASD subtype-commondysregulated pathways. Thesecommonpathways showed a severity gradient with the greatest dysregulation in profound and least in mild. Collectively, results raise the new hypothesis that the continuum of ASD heterogeneity is moderated by subtype-commonpathways and the distinctive nature of profound autism is driven by the differentially added profound subtype-specific embryonic pathways.
Fiber Bragg grating based sensing system for non-destructive root phenotyping using ResNet prediction
Authors: Binder Steven , Hossain Kabir , Bucksch Alexander , Fok Mable
Published: September 2024

Real-time measurements of crop root architecture can overcome limitations faced by plant breeders when developing climate-resilient plants. Due to current measurement methods failing to continuously monitor root growth in a non-destructive and scalable fashion, we propose a first in-soil sensing system based on fiber Bragg gratings (FBG). The sensing system logs three-dimensional strain generated by a growing pseudo-root. Two ResNet models confirm the utility of in-soil FBG sensors by predicting pseudo-root width and depth with accuracies of 92% and 93%, respectively. To analyze model robustness, a preliminary experiment was performed where FBGs logged strain generated from a corn plant's roots for 30 days. The models were then retrained on new data where they achieved accuracies of 98% and 96%, respectively. Our presented prototype has potential prospects to go beyond measuring root parameters and sense its surrounding soil environment.
Application of RFdiffusion to predict interspecies protein-protein interactions between fungal pathogens and cereal crops
Authors: Haley Olivia C. , Harding Stephen , Sen Taner Z. , Woodhouse Margaret R. , Kim Hye-Seon , Andorf Carson
Published: September 2024

Plant pathogenic fungi secrete small proteins known as effectors which help overcome the plant defense response and cause disease. The concept of effector-triggered immunity in plants evolved from the “gene for gene hypothesis” which describes plant resistance or susceptibility to plant pathogens based on interspecies protein-protein interactions (PPIs) between plant-derived resistance (R) genes and pathogen-derived avirulence (Avr) effector genes. Understanding the molecular interactions mediating these host-pathogen interactions in effector-triggered immunity is thus essential to managing fungal disease.In silicomethods of predicting interspecies PPIs have been heavily studied to identify target genes for crop resistance. But conventional sequence-based homology methods (i.e., interlog, domain-based inference) for predicting interspecies PPIs are not as powerful as methods that also incorporate structural homology. The objective of this study was to develop a computational workflow to predict PPIs between pathogenic fungi and their cereal hosts by leveraging recent advances in artificial intelligence and structural biology. This workflow proposes the use of a generative model, RFdiffusion, to predict the structure of truncated segments of proteins likely to bind to query effector proteins. The binder structures were filtered based on the number of contacts at the effectors’ known binding residues. Acceptable structures were then input into FoldSeek to search the host proteome for host proteins containing similar sub-structures. Experimentally-validated PPIs between rice (Oryzae sativacv. ‘Japonica’) and rice blast fungus (Magnaporthe oryzae) were used for workflow validation. The effects of binder length and the binding residues’ mode of action (i.e., residues at active/substrate recognition sites) on the binder quality and presumptive host protein matches were explored. Ultimately, 11 out of 14 experimentally validated PPIs were recovered computationally, indicating a high recall (>78%) for the workflow. The shorter binders recovered most of the PPIs, but may have produced the most false positives, as functional analyses revealed that these host proteins displayed a wide variety of functions. These findings emphasize that subject matter expertise is still required to decipher the prediction results. Yet, this framework for elucidating interactions between fungal pathogens and host proteins could provide valuable insight into mechanisms of susceptibility or resistance at a scale friendly to limited computational resources, and facilitate the development of control strategies that reduce crop diseases.
Variance quantitative trait loci reveal gene-gene interactions which alter blood traits
Authors: Pershad Yash , Poisner Hannah , Corty Robert W , Hellwege Jacklyn N , Bick Alexander G
Published: September 2024

Gene-gene (GxG) interactions play an important role in human genetics, potentially explaining part of the “missing heritability” of polygenic traits and the variable expressivity of monogenic traits. Many GxG interactions have been identified in model organisms through experimental breeding studies, but they have been difficult to identify in human populations. To address this challenge, we applied two complementary variance QTL (vQTL)-based approaches to identify GxG interactions that contribute to human blood traits and blood-related disease risk. First, we used the previously validated genome-wide scale test for each trait in ∼450,000 people in the UK Biobank and identified 4 vQTLs. Genome-wide GxG interaction testing of these vQTLs enabled discovery of novel interactions between (1)CCL24andCCL26for eosinophil count and plasma CCL24 and CCL26 protein levels and (2)HLA-DQA1andHLA-DQB1for lymphocyte count and risk of celiac disease, both of which replicated in ∼140,000 NIH All of Us and ∼70,000 Vanderbilt BioVU participants. Second, we used a biologically informed approach to search for vQTL in disease-relevant genes. This approach identified (1) a known interaction for hemoglobin between two pathogenic variants inHFEwhich cause hereditary hemochromatosis and alters risk of cirrhosis and (2) a novel interaction between theJAK246/1 haplotype and a variant on chromosome 14 which modifies platelet count,JAK2V617F clonal hematopoiesis, and risk of polycythemia vera. This work identifies novel disease-relevant GxG interactions and demonstrates the utility of vQTL-based approaches in identifying GxG interactions relevant to human health at scale.
Severe Sarcoidosis Demonstrates Heterogenous Immune Dysregulation Across Different Peripheral Immune Cell Types: A Single-Center Single Cell Multi-omic Analysis
Authors: Huang Kai , Vagts Christen , Ascoli Christian , Huang Yue , Sweiss Nadera J. , Finn Patricia W. , Perkins David L.
Published: September 2024

Sarcoidosis provides unique management challenges due to variable presentation and disease course. In this single-center analysis, we assess transcriptomic and epigenomic differentiators between severe and mild cases of sarcoidosis using peripheral blood. We showcase differences across multiple cell types that highlight decreased immunoregulation and increased inflammation in severe sarcoidosis. We provide an overall framework for the interactions between immune cells in severe sarcoidosis as a basis for future therapeutic research.

Visual Abstract
Automatically Identifying Event Reports of Workplace Violence and Communication Failures using Large Language Models
Authors: Becker Mike , Hwang Sy , Schriver Emily , Douma Caryn , Duffy Caoimhe , Atkins Joshua , McShane Caitlyn , Lubken Jason , Hanish Asaf , McGreevey John D. , Regli Susan Harkness , Mowery Danielle L.
Published: September 2024

Safety event reporting forms a cornerstone of identifying and mitigating risks to patient and staff safety. However, variabilities in reporting and limited resources to analyze and classify event reports delay healthcare organizations’ ability to rapidly identify safety event trends and to improve workplace safety. We demonstrated how large language models can classify safety event report narratives as workplace violence and communication failures as a first step toward enabling automated labeling of safety event reports and ultimately improving workplace safety.
PANDORA: An AI model for the automatic extraction of clinical unstructured data and clinical risk score implementation
Authors: Castano-Villegas Natalia , Llano Isabella , Jimenez Daniel , Martinez Julian , Ortiz Laura , Velasquez Laura , Zea Jose
Published: September 2024

Introduction

Medical records and physician notes often contain valuable information not organized in tabular form and usually require extensive manual processes to extract and structure. Large Language Models (LLMs) have shown remarkable abilities to understand, reason, and retrieve information from unstructured data sources (such as plain text), presenting the opportunity to transform clinical data into accessible information for clinical or research purposes.

Objective

We present PANDORA, an AI system comprising two LLMs that can extract data and use it with risk calculators and prediction models for clinical recommendations as the final output.

Methods

This study evaluates the model’s ability to extract clinical features from actual clinical discharge notes from the MIMIC database and synthetically generated outpatient clinical charts. We use the PUMA calculator for Chronic Obstructive Pulmonary Disease (COPD) case finding, which interacts with the model and the retrieved information to produce a score and classify patients who would benefit from further spirometry testing based on the 7 items from the PUMA scale.

Results

The extraction capabilities of our model are excellent, with an accuracy of 100% when using the MIMIC database and 99% for synthetic cases. The ability to interact with the PUMA scale and assign the appropriate score was optimal, with an accuracy of 94% for both databases. The final output is the recommendation regarding the risk of a patient suffering from COPD, classified as positive according to the threshold validated for the PUMA scale of equal to or higher than 5 points. Sensitivity was 86% for MIMIC and 100% for synthetic cases.

Conclusion

LLMs have been successfully used to extract information in some cases, and there are descriptions of how they can recommend an outcome based on the researcher’s instructions. However, to the best of our knowledge, this is the first model which successfully extracts information based on clinical scores or questionnaires made and validated by expert humans from plain, non-tabular data and provides a recommendation mixing all these capabilities, using not only knowledge that already exists but making it available to be explored in light of the highest quality evidence in several medical fields.
The Human Cytomegalovirus vGPCR UL33 is Essential for Efficient Lytic Replication in Epithelial Cells
Authors: Freeman MacKenzie R. , Dooley Abigail L. , Beucler Matthew J. , Sanders Wes , Moorman Nathaniel J. , O’Connor Christine M. , Miller William E.
Published: September 2024

Human cytomegalovirus (HCMV) is a β-herpesvirus which is ubiquitous in the human population. HCMV has the largest genome of all known human herpesviruses, and thus encodes a large array of proteins that affect pathogenesis in different cell types. Given the large genome and the ability of HCMV to replicate in a range of cells, investigators have begun to identify viral proteins required for cell type-specific replication. There are four proteins encoded in the HCMV genome that are homologous to human G protein-coupled receptors (GPCRs); these viral-encoded GPCRs (vGPCRs) are UL33, UL78, US27, and US28. In the current study, we find that deletion of all four vGPCR genes from a clinical isolate of HCMV severely attenuates lytic replication in both primary human salivary gland epithelial cells, as well as ARPE-19 retinal epithelial cells as evidenced by significant decreases in immediate early gene expression and virus production. Deletion of UL33 from the HCMV genome also results in a failure to efficiently replicate in epithelial cells, and this defect is manifested by decreased levels of immediate early, early, and late gene expression, as well as reduced viral production. We find that similar to US28, UL33 constitutively activates Gαq-dependent PLC-β signaling to high levels in these epithelial cells. We also find that UL33 transcription is more complicated than originally believed, and there is the potential for the virus to utilize various 5’ UTRs to create novel UL33 proteins that are all capable of constitutive Gαq signaling. Taken together, these studies suggest that UL33 driven signaling is important for lytic HCMV replication in cells of epithelial origin.
Lateralized cerebellar connectivity differentiates auditory pathways in echolocating and non-echolocating whales
Authors: Flem Sophie , Berns Gregory , Inglis Ben , Niederhut Dillon , Montie Eric , Deacon Terrence , Miller Karla L. , Tyack Peter , Cook Peter F.
Published: September 2024

We report the first application of diffusion tractography to a mysticete, which was analyzed alongside three odontocete brains, allowing the first direct comparison of strength and laterality of auditory pathways in echolocating and non-echolocating whales. Brains were imaged post-mortem at high resolution with a specialized steady state free precession diffusion sequence optimized for dead tissue. We conducted probabilistic tractography to compare the qualitative features, tract strength, and lateralization of potential ascending and descending auditory paths in the mysticete versus odontocetes. Tracts were seeded in the inferior colliculi (IC), a nexus for ascending auditory information, and the cerebellum, a center for sensorimotor integration. Direct IC to temporal lobe pathways were found in all animals, replicating previous cetacean tractography and suggesting conservation of the primary auditory projection path in the cetacean clade. Additionally, odontocete IC-cerebellum pathways exhibited higher overall tract strength than in the mysticete, suggesting a role as descending acousticomotor tracts supporting the rapid sensorimotor integration demands of echolocation. Further, in the mysticete, contralateral right IC to left cerebellum pathways were 17x stronger than those between left IC and right cerebellum, while in odontocetes, the laterality was reversed, and left IC to right cerebellum pathways were 2-4x stronger than those between right IC and left cerebellum. The stronger left IC-right cerebellum connectivity observed in odontocetes corroborates the theory that odontocetes preferentially echolocate with their right phonic lips, as the right phonic lips are likely innervated by left-cortical motor efferents that integrate with left-cortical auditory afferents in right cerebellum. This interpretation is further supported by the reversed lateralization of IC-cerebellar tracts observed in the non-echolocating mysticete. We also found differences in the specific subregions of cerebellum targeted by the IC, both between the mysticete and odontocetes, and between left and right sides. This study establishes foundational knowledge on mysticete auditory connectivity and extends knowledge on the neural basis of echolocation in odontocetes.
Human macula formation involves two waves of retinoic acid signaling suppression viaCYP26A1regulating cell cycle exit and cone specification
Authors: Harding Philippa , Wojtynska Maja , Smith Alexander J. , Ali Robin R. , Pearson Rachael A.
Published: September 2024

The human macula is a specialized, M/L cone-rich region of the eye, critical for high acuity vision, but little is known about the pathways regulating its development. Transcriptional regulation by Retinoic Acid (RA) is essential for many aspects of human eye development. Here, we report a striking biphasic expression of the RA-catabolizing enzyme,CYP26A1,in early human macular development between post-conception weeks 6-17. Early inhibition of RA signaling in human retinal organoids (hROs) prompts early cell cycle exit, and an increase in cone photoreceptors, while late inhibition alters cone subtype specification. Conversely,FGF8,which is negatively regulated by RA and vital for High Acuity Area specification in chick, is not expressed in the nascent human macula and had no effect on hRO photoreceptor fate.

Graphical abstract
Dopamine release in striatal striosome compartments in response to rewards and aversive outcomes during classical conditioning in mice
Authors: Yoshizawa Tomohiko , Funahashi Makoto
Published: September 2024

The striatum consists of two anatomically and neurochemically distinct compartments, striosomes and the matrix, which receive dopaminergic inputs from the midbrain and exhibit distinct dopamine release dynamics in acute brain slices. Striosomes comprise approximately 15% of the striatum by volume and are distributed mosaically. Therefore, it is difficult to selectively record dopamine dynamics in striosomes using traditional neurochemical measurements in behaving animals, and it is unclear whether distinct dynamics play a role in associative learning. In this study, we used transgenic mice selectively expressing Cre in striosomal neurons, combined with a fiber photometry technique, to selectively record dopamine release in striosomes during classical conditioning. Water-restricted mice could distinguish the conditioned stimulus (CS) associated with saccharin water from the air-puff-associated CS. The air-puff-associated CS evoked phasic dopamine release only in striosomes. Furthermore, air puff presentation induced dopamine release to striosomal neurons but suppressed release to putative matrix neurons. These findings suggest that dopamine is released in a differential manner in striosomes and the matrix in behaving animals and that dopamine release in striosomes is preferentially induced by the air-puff-associated CS and air puff presentation. These findings support the hypothesis that striosomal neurons play a dominant role in aversive stimuli prediction.

Highlights

Dopamine (DA) release was successfully measured in striosomes of behaving mice.

A conditioned stimulus for aversive outcomes induced DA release in striosomes.

In striosomes, rewarding and aversive unconditioned stimuli triggered DA release.
Conserved ancillary residues situated proximally to the VIM-2 active site affect its metallo β-lactamase activity
Authors: Jain Diamond , Ajith Tejavath , Verma Jyoti , Chatterjee Debasmita , Ghosh Anindya S.
Published: September 2024

Verona-integron-metallo-β-lactamase (VIM-2) is one of the most widespread class B β-lactamase, responsible for β-lactam resistance. Although active-site residues help in metal binding, the residues nearing the active-site possess functional importance. Here, to decipher the role of such residues in the activity and stability of VIM-2, the residues E146, D182, N210, S207, and D213 were selected through in-silico analyses and substituted with alanine using site-directed mutagenesis. The effects of substitution mutations were assessed by comparing the changes in the β-lactam susceptibility pattern of E. coli host cells expressing VIM-2 and its mutated proteins. VIM-2_N210A enhanced the susceptibility of the host by ∼4-8 folds against penicillins and cephalosporins while the expression of VIM-2_D182A radically increased the susceptibility of the host. However, expression of VIM-2_E146A reduced the susceptibility of the host by 2-fold. Further, proteins were purified to homogeneity, and VIM_N210A and VIM_D182A displayed reduced thermal stability than VIM-2. Moreover, in vitro catalytic efficiencies of VIM-2_D182A were drastically reduced against all the β-lactams tested whereas the same were moderately reduced for VIM-2_N210A. Conversely, the catalytic efficiency was marginally altered for VIM_E146A. Overall, we infer that both N210A and D182A substitutions negatively affect the performance of VIM-2 by influencing substrate specificity and stability, respectively.