bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma
Authors: Licón-Muñoz Y. , Avalos V. , Subramanian S. , Granger B. , Martinez F. , Varela S. , Moore D. , Perkins E. , Kogan M. , Berto S. , Chohan M.O. , Bowers C.A. , Piccirillo S.G.M.
Published: April 2024

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on theZEB1regulatory network, whereas tumor cells in the T_Mass relied on theTEAD1regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.
The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength
Authors: Zimmer Stephanie E. , Giang William , Levental Ilya , Kowalczyk Andrew P.
Published: April 2024

Cholesterol- and sphingolipid-enriched domains called lipid rafts are hypothesized to selectively coordinate protein complex assembly within the plasma membrane to regulate cellular functions. Desmosomes are mechanically resilient adhesive junctions that associate with lipid raft membrane domains, yet the mechanisms directing raft association of the desmosomal proteins, particularly the transmembrane desmosomal cadherins, are poorly understood. We identified the desmoglein-1 (DSG1) transmembrane domain (TMD) as a key determinant of desmoglein lipid raft association and designed a panel of DSG1TMDvariants to assess the contribution of TMD physicochemical properties (length, bulkiness, and palmitoylation) to DSG1 lipid raft association. Sucrose gradient fractionations revealed that TMD length and bulkiness, but not palmitoylation, govern DSG1 lipid raft association. Further, DSG1 raft association determines plakoglobin recruitment to raft domains. Super-resolution imaging and functional assays uncovered a strong relationship between the efficiency of DSG1TMDlipid raft association and the formation of morphologically and functionally robust desmosomes. Lipid raft association regulated both desmosome assembly dynamics and DSG1 cell surface stability, indicating that DSG1 lipid raft association is required for both desmosome formation and maintenance. These studies identify the biophysical properties of desmoglein transmembrane domains as key determinants of lipid raft association and desmosome adhesive function.
Increased host diversity limits bacterial generalism but may promote microbe-microbe interactions
Authors: Holmes Iris A , Martínez-Fonseca José G , von May Rudolf , Sealey Briana A , Cerda Peter A , Grundler Maggie R , Westeen Erin P , Nondorf Daniel , Larson Joanna G , Myers Christopher R , Hendry Tory A
Published: April 2024

Host-associated bacteria vary in their host breadth, which can impact ecological interactions. By colonizing diverse hosts, host generalists can have disproportionate ecological impacts. For bacteria, host generalism may advantageous, particularly when the availability of specific hosts is variable. It is unclear how much the ability to evolve generalism, by inhabiting diverse hosts, is constrained in host-associated bacteria. We hypothesized that constraints on bacterial generalism will differ depending on the availability of specific host species. To test this, we assessed patterns of diversity and specialization in the cloacal microbiomes of reptile communities from the temperate zone to the tropics, where the diversity and abundance of host species varies substantially. Within these communities, generalist taxa tended to be Proteobacteria, whereas specialists tended to be Firmicutes. We found that bacterial generalists were less prevalent in the highest diversity host communities, and in keeping with this, Proteobacteria were less diverse in these communities. Generalist taxa became relatively less widespread across host species only in the two most diverse host communities. We therefore conclude that the constraint on generalism is not driven by absolute incompatibility with some host species, but rather from competition with host adapted specialist lineages. In the high-diversity communities, we found that the successful generalists, typically Proteobacteria, were disproportionately likely to co-occur with one another across evolutionarily disparate hosts within the community. Our data indicate that bacterial lineages can adapt to the evolutionary pressures of high diversity host communities either by specializing on hosts or by forming cohorts of co-occurring bacterial lineages.
CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer
Authors: Zhong Chunge , Jiang Wen-Jie , Yao Yingjia , Li Zexu , Li You , Wang Shengnan , Wang Xiaofeng , Zhu Wenjuan , Wu Siqi , Wang Jing , Fan Shuangshuang , Ma Shixin , Liu Yeshu , Zhang Han , Zhao Wenchang , Zhao Lu , Feng Yi , Li Zihan , Guo Ruifang , Yu Li , Pei Fengyun , Hu Jun , Feng Xingzhi , Yang Zihuan , Yang Zhengjia , Yang Xueying , Hou Yue , Zhang Danni , Xu Dake , Sheng Ren , Li Yihao , Liu Lijun , Wu Hua-Jun , Huang Jun , Fei Teng
Published: April 2024

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.
Sex Differences in Pulmonary Hypertension and Associated Right Ventricular Dysfunction
Authors: Ma Janet I. , Owunna Ndidi , Jiang Nona M. , Huo Xiaodan , Zern Emily , McNeill Jenna N. , Lau Emily S. , Pomerantsev Eugene , Picard Michael H. , Wang Dongyu , Ho Jennifer E.
Published: April 2024

Background

Prior studies have established the impact of sex differences on pulmonary arterial hypertension (PAH). However, it remains unclear whether these sex differences extend to other hemodynamic subtypes of pulmonary hypertension (PH).

Methods

We examined sex differences in PH and hemodynamic PH subtypes in a hospital-based cohort of individuals who underwent right heart catheterization between 2005-2016. We utilized multivariable linear regression to assess the association of sex with hemodynamic indices of RV function [PA pulsatility index (PAPi), RV stroke work index (RVSWI), and right atrial: pulmonary capillary wedge pressure ratio (RA:PCWP)]. We then used Cox regression models to examine the association between sex and clinical outcomes among those with PH.

Results

Among 5208 individuals with PH (mean age 64 years, 39% women), there was no significant sex difference in prevalence of PH overall. However, when stratified by PH subtype, 31% of women vs 22% of men had pre-capillary (P<0.001), 39% vs 51% had post-capillary (P=0.03), and 30% vs 27% had mixed PH (P=0.08). Female sex was associated with better RV function by hemodynamic indices, including higher PAPi and RVSWI, and lower RA:PCWP ratio (P<0.001 for all). Over 7.3 years of follow-up, female sex was associated with a lower risk of heart failure hospitalization (HR 0.83, CI 95% CI 0.74– 0.91, p value <0.001).

Conclusions

Across a broad hospital-based sample, more women had pre-capillary and more men had post-capillary PH. Compared with men, women with PH had better hemodynamic indices of RV function and a lower risk of HF hospitalization.

CLINICAL PERSPECTIVE

What Is New?

Although sex differences have been explored in pulmonary arterial hypertension, sex differences across pulmonary hypertension (PH) in broader samples inclusive of all hemodynamic subtypes remain less well defined

We delineate sex differences in hemodynamic subtypes of PH and associated right ventricular function in a large, heterogenous, hospital-based sample of individuals who underwent right heart catheterization

Sex has a significant impact on prevalence of PH across hemodynamic subtypes as well as associated RV function

What Are the Clinical Implications?

Understanding sex differences across different PH hemodynamic subtypes is paramount to refining risk stratification between men and women

Further elucidating sex differences in associated RV function and clinical outcomes may aid in developing sex-specific therapies or management strategies to improve clinical outcomes
Personalizing supportive healthcare for patients with immunological disorders
Authors: Folkertsma Tessa S. , Bos Reinhard , Vodegel Robert M. , Bloem Sjaak , Liefveld Aad R. , Tack Greetje J.
Published: April 2024

Current insights to personalize supportive care for patients with immunological disorders, especially in the context of medical treatments, remain inadequate. Delivering and guiding supportive care unquestionably contributes to a higher quality of life and better overall healthcare. The ‘Subjective Health Experience (SHE) Model’ provides a general framework, comprising four segments, to differentiate supportive healthcare in a quick and practical approach. In this report both health care workers and patients tailored the unique needs of patients with immunological disorders to improve their supportive care.

Employing qualitative methods, group discussions and individual interviews were conducted with 19 healthcare professionals and 18 patients suffering from Rheumatoid Arthritis/Spondylarthritis, Inflammatory Bowel Disease (Crohn’s disease and Ulcerative colitis), and Psoriasis/Hidradenitis Suppurativa. The aim was to ascertain nuanced insights into the behaviour, questions, and needs of patients with six common immunological conditions guided by the SHE-model, thereby refining the personalized supportive care framework.

A detailed description was made for patients with immunological disorders per SHE-model segment. Based on these insights, it was determined for each segment‘WHAT’kind of supportive care is needed and‘HOW’it should be offered. Notably, patients emphasized the qualitative aspects of their interactions with healthcare professionals (attention, acknowledgment, and empathetic communication), contrasting with professionals’ focus on the treatment plan. This led to a strategic allocation of supportive care interventions across patient segments.

This study has significantly advanced our understanding of appropriate supportive healthcare for patients with immunological disorders from the perspective of the SHE-model. These findings not only enrich the existing literature but also equip healthcare professionals with a concrete guide for enhancement of supportive care, as the SHE-model is easy to perform in daily clinical care. Attention, acknowledgment, and listening comprise the foundational elements for offering and guiding supportive care.
Combining transformer and 3DCNN models to achieve co-design of structures and sequences of antibodies in a diffusional manner
Authors: Hu Yue , Tao Feng , Lan WenJun , Zhang Jing
Published: April 2024

Antibody drugs are among the fastest growing therapeutic modalities in modern drug research and development. Due to the huge search space of antibody sequences, the traditional experimental screening method cannot fully meet the needs of antibody discover. More and more rational design methods have been proposed to improve the success rate of antibody drugs. In recent years, artificial intelligence methods have increasingly become an important means of rational design. We have proposed an algorithm for antibody design, called AlphaPanda (AlphaFold2 inspired Protein-specific antibody design in a diffusional manner). The algorithm mainly combines the transformer model, the 3DCNN model and the diffusion generative model, use the transformer model to capture the global information and uses the 3DCNN model to capture the local structural characteristics of the antibody-antigen complexes, and then uses the diffusion model to generate sequences and structures of antibodies. The 3DCNN model can capture pairwise interactions in antibody-antigen complex, as well as non-pairwise interactions in antibody-antigen complex, and it requires less training sample data, while avoiding the defects of the generation progress by the autoregressive model and by the self-consistent iterative model. Diffusion generative model can generate sequence and structure effectively and with high quality. By combining 3DCNN method and diffusion model method, we have achieved the integration of 3DCNN model to the protein design with flexible main chains. By utilizing the advantages of these aspects, a good performance has been achieved by the AlphaPanda algorithm. The algorithm we propose can not only be applied to antibody design, but also be more widely applied to various fields of other protein design. The source code can be get from github (https://github.com/YueHuLab/AlphaPanda).
SAMP: Identifying Antimicrobial Peptides by an Ensemble Learning Model Based on Proportionalized Split Amino Acid Composition
Authors: Feng Junxi , Sun Mengtao , Liu Cong , Zhang Weiwei , Xu Changmou , Wang Jieqiong , Wang Guangshun , Wan Shibiao
Published: April 2024

Abstract

It is projected that 10 million deaths could be attributed to drug-resistant bacteria infections in 2050. To address this concern, identifying new-generation antibiotics is an effective way. Antimicrobial peptides (AMPs), a class of innate immune effectors, have received significant attention for their capacity to eliminate drug-resistant pathogens, including viruses, bacteria, and fungi. Recent years have witnessed widespread applications of computational methods especially machine learning (ML) and deep learning (DL) for discovering AMPs. However, existing methods only use features including compositional, physiochemical, and structural properties of peptides, which cannot fully capture sequence information from AMPs. Here, we present SAMP, an ensemble random projection (RP) based computational model that leverages a new type of features called Proportionalized Split Amino Acid Composition (PSAAC) in addition to conventional sequence-based features for AMP prediction. With this new feature set, SAMP captures the residue patterns like sorting signals at around both the N-terminus and the C-terminus, while also retaining the sequence order information from the middle peptide fragments. Benchmarking tests on different balanced and imbalanced datasets demonstrate that SAMP consistently outperforms existing state-of-the-art methods, such as iAMPpred and AMPScanner V2, in terms of accuracy, MCC, G-measure and F1-score. In addition, by leveraging an ensemble RP architecture, SAMP is scalable to processing large-scale AMP identification with further performance improvement, compared to those models without RP. To facilitate the use of SAMP, we have developed a Python package freely available athttps://github.com/wan-mlab/SAMP.
An amyloidogenic fragment of the SARS CoV-2 envelope protein promotes serum amyloid A misfolding and fibrillization
Authors: Nady Asal , Reichheld Sean E. , Sharpe Simon
Published: April 2024

SARS CoV-2 infection can affect a surprising number of organs in the body and cause symptoms such as abnormal blood coagulation, fibrinolytic disturbances, and neurodegeneration. Our study delves into the intricate pathogenic potential of a SARS-CoV-2 envelope protein peptide, shedding light on its implications for multi-organ effects and amyloid formation. Specifically, we focus on the peptide SK9 or54SFYVYSRVK62derived from the C-terminus of human SARS coronavirus 2 envelope protein. We demonstrate that SK9 containing peptides readily form classic amyloid structures consistent with predictions of amyloid aggregation algorithms.In vivo, overexpression of proteases such as neutrophil elastase during inflammation can potentially lead to C-terminal peptides containing SK9. We also demonstrate that SK9 can promote the fibrillization of SAA, a protein marker of acute inflammation. Our investigations reveal that the aromatic residues Phe2 and Tyr3 of SK9 play a pivotal role in its amyloidogenic function. We show that the primary sites of SK9-SAA binding lie in the amyloidogenic hotspots of SAA itself. Our results highlight two possible complications of SARS CoV-2 infection in individuals with hyper-inflammation either due to amyloids arising from SK9 containing peptides or SK9-induced AA amyloidosis.
The T3SS structural and effector genes ofChlamydia trachomatisare expressed in distinct phenotypic cell forms
Authors: Grieshaber Nicole A. , Appa Cody , Ward Megan , Grossman Alorah , McCormik Sean , Grieshaber Brendan S. , Chiarelli Travis , Yang Hong , Omsland Anders , Grieshaber Scott S.
Published: April 2024

Bacteria in the chlamydiales order are obligate intracellular parasites of eukaryotic cells. Within this order, the genusChlamydiacontains the causative agents of a number of clinically important infections of humans. Biovars ofC. trachomatisare the causative agents of trachoma, the leading cause of preventable blindness worldwide, as well as sexually transmitted infections with the potential to cause pelvic inflammatory disease and infertility. Irrespective of the resulting disease, all chlamydial species share the same obligate intracellular life cycle and developmental cell forms. They are reliant on an infectious cycle consisting of at least three phenotypically distinct cell forms termed the reticulate body (RB), the intermediate body (IB) and the elementary body (EB). The EB is infectious but does not replicate. The RB replicates in the host cell but is non-infectious, while the IB is an intermediate form that transitions to the EB form. In this study, we ectopically expressed the transcriptional repressor Euo, the two nucleoid-associated proteins HctA and HctB, and the two component sensor kinase CtcB in the RB. Transcriptional analysis using RNA-seq, differential expression clustering and fluorescencein situhybridization analysis show that the chlamydial developmental cycle is driven by three distinct regulons corresponding to the RB, IB or EB cell forms. Moreover, we show that the genes for the T3SS were cell type restricted, suggesting defined functional roles for the T3SS in specific cell forms.

Importance

Chlamydia trachomatis, a sexually transmitted bacterial infection, poses a significant global health threat, causing over 100 million infections annually and leading to complications like ectopic pregnancy and infertility. This study investigates the gene expression patterns ofChlamydia trachomatisduring its unique life cycle within human cells. As an obligate intracellular parasite,C. trachomatistransitions through distinct developmental stages - one for infection and dissemination, another for replication, and a third for transitioning back to the infectious form. By analyzing gene expression profiles at each stage, we identified key genes involved in these processes. Interestingly, our research also reveals the presence of two separate T3SS (Type III Secretion System) translocons expressed in distinct stages, suggesting their crucial roles in specific functions during the infection cycle.
A Conserved Inhibitory Interdomain Interaction Regulates DNA-binding Activities of Hybrid Two-component Systems inBacteroides
Authors: Gao Rong , Wu Ti , Stock Ann M.
Published: April 2024

Hybrid two-component systems (HTCSs) comprise a major class of transcription regulators of polysaccharide utilization genes inBacteroides. Distinct from classical two-component systems in which signal transduction is carried out by intermolecular phosphotransfer between a histidine kinase (HK) and a cognate response regulator (RR), HTCSs contain the membrane sensor HK and the RR transcriptional regulator within a single polypeptide chain. Tethering the DNA-binding domain (DBD) of the RR with the dimeric HK domain in an HTCS could potentially promote dimerization of the DBDs and would thus require a mechanism to suppress DNA-binding activity in the absence of stimulus. Analysis of phosphorylation and DNA-binding activities of several HTCSs fromBacteroides thetaiotaomicronrevealed a DBD-suppression mechanism in which an inhibitory interaction between the DBD and the phosphoryl group-accepting receiver domain (REC) decreases autophosphorylation rates of HTCS-RECs as well as represses DNA-binding activities in the absence of phosphorylation. Sequence analyses and structure predictions identified a highly conserved sequence motif correlated with a conserved inhibitory domain arrangement of REC and DBD. Presence of the motif, as in most HTCSs, or its absence, in a small subset of HTCSs, is likely predictive of two distinct regulatory mechanisms evolved for different glycans. Substitutions within the conserved motif relieve the inhibitory interaction and result in elevated DNA-binding activities in the absence of phosphorylation. Our data suggest a fundamental regulatory mechanism shared by most HTCSs to suppress DBD activities using a conserved inhibitory interdomain arrangement to overcome the challenge of the fused HK and RR components.

Importance

Different dietary and host-derived complex carbohydrates shape the gut microbial community and impact human health. InBacteroides, the prevalent gut bacteria genus, utilization of these diverse carbohydrates relies on different gene clusters that are under sophisticated control by various signaling systems, including the hybrid two-component systems (HTCSs). We have uncovered a highly conserved regulatory mechanism in which the output DNA-binding activity of HTCSs is suppressed by interdomain interactions in the absence of stimulating phosphorylation. A consensus amino acid motif is found to correlate with the inhibitory interaction surface while deviations from the consensus can lead to constitutive activation. Understanding of such conserved HTCS features will be important to make regulatory predictions for individual systems as well as to engineer novel systems with substitutions in the consensus to explore the glycan regulation landscape inBacteroides.
Long-sperm precedence and other cryptic female choices inDrosophila melanogaster
Authors: Peckenpaugh Brooke , Yew Joanne Y , Moyle Leonie C
Published: April 2024

Females that mate multiply make postmating choices about which sperm fertilize their eggs (cryptic female choice); however, the male characteristics they use to make such choices remain unclear. In this study, we sought to understand female sperm use patterns by evaluating whetherDrosophila melanogasterfemales adjust sperm use (second male paternity) in response to four main factors: male genotype, male courtship effort, male pheromone alteration, and male postmating reproductive morphology. Our experiment was replicated across four differentD. melanogasterlines, in a full factorial design, including a pheromone manipulation in which second males were perfumed to resemble heterospecific (D. yakuba) males. We found that females prefer longer sperm—regardless of mating order—in almost all contexts; this observed pattern of 'long-sperm precedence' is consistent with female postcopulatory choice of high-fitness male traits. Nonetheless, we also found that this general preference can be plastically altered by females in response to effects including perfuming treatment; this differential female sperm use is between otherwise identical males, and therefore solely female-mediated. Furthermore, our finding that females exercise choice using diverse criteria suggests a possible mechanism for the maintenance of variation in sexually selected male traits.
Modification of Azithromycin to Mitigate its Arrest of Autophagy
Authors: Quarrington Ryan D , Sapula Sylvia A , Lester Susan E , Miller Matthew M , Munic Kos Vesna , Kopp Benjamin T , Jersmann Hubertus PA , Blencowe Anton , Roscioli Eugene
Published: April 2024

Aims/hypothesi

Autophagy plays a critical role in the survival and microbial clearance functions of airway epithelial cells (AECs). Contrary to the known roles of azithromycin (AZM) in promoting microbial clearance, our preliminary evidence suggests that AZM inhibits autophagy in mammalian cells ‒ an effect that could potentially promote bacterial residency in chronic respiratory diseases. Here we investigate the structure-activity relationship of AZMvsother common macrolides and AZM-3’-N-oxide (AZM-[O]), to mitigate the off-target arrest of autophagy.

Method

Participant-derived chronic obstructive pulmonary disease (COPD)vscontrol airway biopsies were assessed for intrinsic defects in autophagy gene activity via qRT-PCR array. Forin vitrostudies, the 16HBE14o-AEC line and Western blot were used to assess macrolidevsautophagy structure-activity relationships, and autophagic flux by quantifying the protein abundance of LC3B-IIvsSequestosome-1. Subsequent assessments of antimicrobial activity were conducted using anE. colimodel and the micro-broth dilution method. Immunomodulatory outcomes were assessed by quantifying the secretion of IL-6 in a lipopolysaccharide LPS-stimulated THP-1 macrophage model.

Results

Signatures of transcript-abundance showed an overall reduction in autophagy gene activity in COPDvscontrol biopsies. AZM significantly inhibited autophagic flux, evidenced by the accumulation of LC3B-II and Sequestosome-1, compared to its precursors and other macrolides including roxithromycin and clarithromycin. Notably, oxidation of AZM to produce AZM-[O] significantly alleviated this inhibitory effect on autophagy without completely preserving its antimicrobial and immunomodulatory functions.

Conclusion

The potent off-target block of autophagic flux demonstrated by AZM can be negated by manipulation of its ionisation state. We are currently investigating the AZM-protein interactome and further AZM derivatives that preserve the immunomodulatory function of the parent molecule, to provide a new therapeutic option for chronic respiratory disease and to safeguard the efficacy of AZM.
Predicting Risk of Alzheimer’s Diseases and Related Dementias with AI Foundation Model on Electronic Health Records
Authors: Zhu Weicheng , Tang Huanze , Zhang Hao , Rajamohan Haresh Rengaraj , Huang Shih-Lun , Ma Xinyue , Chaudhari Ankush , Madaan Divyam , Almahmoud Elaf , Chopra Sumit , Dodson John A. , Brody Abraham A. , Masurkar Arjun V. , Razavian Narges
Published: April 2024

Early identification of Alzheimer’s disease (AD) and AD-related dementias (ADRD) has high clinical significance, both because of the potential to slow decline through initiating FDA-approved therapies and managing modifiable risk factors, and to help persons living with dementia and their families to plan before cognitive loss makes doing so challenging. However, substantial racial and ethnic disparities in early diagnosis currently lead to additional inequities in care, urging accurate and inclusive risk assessment programs. In this study, we trained an artificial intelligence foundation model to represent the electronic health records (EHR) data with a vast cohort of 1.2 million patients within a large health system. Building upon this foundation EHR model, we developed a predictive Transformer model, namedTRADE, capable of identifying risks for AD/ADRD and mild cognitive impairment (MCI), by analyzing the past sequential visit records. Amongst individuals 65 and older, our model was able to generate risk predictions for various future timeframes. On the held-out validation set, our model achieved an area under the receiver operating characteristic (AUROC) of 0.772 (95% CI: 0.770, 0.773) for identifying the AD/ADRD/MCI risks in 1 year, and AUROC of 0.735 (95% CI: 0.734, 0.736) in 5 years. The positive predictive values (PPV) in 5 years among individuals with top 1% and 5% highest estimated risks were 39.2% and 27.8%, respectively. These results demonstrate significant improvements upon the current EHR-based AD/ADRD/MCI risk assessment models, paving the way for better prognosis and management of AD/ADRD/MCI at scale.
Increased Resting Brain Entropy in Mild to Moderate Depression was Decreased by Nonpharmacological Treatment
Authors: Song Dong-Hui , Wang Yin , Wang Ze
Published: April 2024

Entropy indicates systematic irregularity and information capacity. Recent years have seen increasing interest in assessing regional brain entropy (BEN) using fMRI in healthy controls (HCs) and patients with various brain diseases. Depression and anti-depressant related BEN alterations have been reported in several initial studies. Re-examining these effects using independent cohort is crucial given the high complexity of depression. In this study, we used open data from OpenNeuro from 46 mild to moderate depression patients and 20 HCs to examine regional BEN and its changes due to nonpharmacological treatment (14 patients underwent nonpharmacological treatment). Functional connectivity (FC) analysis was performed to assess the inter-regional relationship between the brain regions showing BEN effects and the rest of the brain. Compared to HCs, depression patients showed increased BEN in left DLPFC, precuneus, and limbic system, including the amygdala, parahippocampal gyrus and hippocampus. Increased BEN in DLPFC, precuneus, and amygdala were suppressed by a nonpharmacological treatment in each individual patient. HCs had positive FC between left and right DLPFC and negative FC between left DLPFC and limbic areas, while patients had abnormally lower or negative FC between left and right DLPFC and positive FC between left DLPFC and the limbic area. These left DLPFC seeded FC changes in patients were reverted after nonpharmacological treatment. The findings highlight the left DLPFC and limbic system in depression and the treatment effects, and patients with depression exhibit significant emotion dysregulation, which is effectively addressed by nonpharmacological treatment targeting the top-down emotion regulation functions mediated by the DLPFC-limbic system. Different from existing literature, these results suggest the entropy/irregularity of DLPFC and limbic system as a potential mechanism underlying depression and suggest BEN in left DLPFC as a potential personalized marker for assessing depression and the corresponding nonpharmacological treatment effects.
Measuring the Impact of Medical Cannabis Law Adoption on Employer-sponsored Health Insurance Costs: A Difference-in-Difference analysis, 2003-2022
Authors: Doucette Mitchell L. , Hemraj Dipak , Fisher Emily , Macfarlan D. Luke
Published: April 2024

Introduction

Recent studies suggest that medical cannabis laws might contribute to a reduction in health insurance costs within the individual health insurance markets at the state level. We investigated the effects of adopting a medical cannabis law on the cost of employer-sponsored health insurance.

Methods

We analyzed state-level data from the Medical Expenditure Panel Survey - Insurance Component (MEPS-IC) Private Sector spanning from 2003 to 2022. The outcomes included log transformed average total premiums per employee for single, employee-plus-one, and family coverage plans. We utilized the Sun and Abraham (2021) difference-in-difference (DiD) method, looking at the overall DiD and event-study DiD. Models were adjusted for various state-level demographics and dichotomous policy variables including whether a state later adopted recreational cannabis as well as time and unit fixed effects and population weights.

Results

For states that adopted a medical cannabis law, there was a significant decrease in the log average total premium per employee for single (-0.034, standard error [SE] = 0.009) and employee plus one (-0.025, SE = 0.009) coverage plans considering the first 10 years of policy change compared to states without such laws. Looking at the last five years of policy change, we saw increases in effect size and statistical significance. Sensitivity analyses suggest findings are robust to our model specifications.

Discussion

Adoption of a medical cannabis law may contribute to decreases in healthcare costs. This phenomenon is likely a secondary effect and suggests positive externalities outside of medical cannabis patients.

Key Points

States that passed medical cannabis laws, compared to states that did not pass such laws, saw decreases in the average total costs for employer-sponsored health insurance premiums.

The difference in average total costs for employer-sponsored health insurance premiums, comparing states with and without medical cannabis laws, grew over time.

This paper contributes to the idea that medical cannabis laws may contain positive externalities.
A Systematic Review of ChatGPT and Other Conversational Large Language Models in Healthcare
Authors: Wang Leyao , Wan Zhiyu , Ni Congning , Song Qingyuan , Li Yang , Clayton Ellen Wright , Malin Bradley A. , Yin Zhijun
Published: April 2024

Background

The launch of the Chat Generative Pre-trained Transformer (ChatGPT) in November 2022 has attracted public attention and academic interest to large language models (LLMs), facilitating the emergence of many other innovative LLMs. These LLMs have been applied in various fields, including healthcare. Numerous studies have since been conducted regarding how to employ state-of-the-art LLMs in health-related scenarios to assist patients, doctors, and public health administrators.

Objective

This review aims to summarize the applications and concerns of applying conversational LLMs in healthcare and provide an agenda for future research on LLMs in healthcare.

Methods

We utilized PubMed, ACM, and IEEE digital libraries as primary sources for this review. We followed the guidance of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) to screen and select peer-reviewed research articles that (1) were related to both healthcare applications and conversational LLMs and (2) were published before September 1st, 2023, the date when we started paper collection and screening. We investigated these papers and classified them according to their applications and concerns.

Results

Our search initially identified 820 papers according to targeted keywords, out of which 65 papers met our criteria and were included in the review. The most popular conversational LLM was ChatGPT from OpenAI (60), followed by Bard from Google (1), Large Language Model Meta AI (LLaMA) from Meta (1), and other LLMs (5). These papers were classified into four categories in terms of their applications: 1) summarization, 2) medical knowledge inquiry, 3) prediction, and 4) administration, and four categories of concerns: 1) reliability, 2) bias, 3) privacy, and 4) public acceptability. There are 49 (75%) research papers using LLMs for summarization and/or medical knowledge inquiry, and 58 (89%) research papers expressing concerns about reliability and/or bias. We found that conversational LLMs exhibit promising results in summarization and providing medical knowledge to patients with a relatively high accuracy. However, conversational LLMs like ChatGPT are not able to provide reliable answers to complex health-related tasks that require specialized domain expertise. Additionally, no experiments in our reviewed papers have been conducted to thoughtfully examine how conversational LLMs lead to bias or privacy issues in healthcare research.

Conclusions

Future studies should focus on improving the reliability of LLM applications in complex health-related tasks, as well as investigating the mechanisms of how LLM applications brought bias and privacy issues. Considering the vast accessibility of LLMs, legal, social, and technical efforts are all needed to address concerns about LLMs to promote, improve, and regularize the application of LLMs in healthcare.
Safety, Pharmacokinetics, Biomarker Response, and Efficacy of E6742, a Dual Antagonist of Toll-Like Receptors 7 and 8, in a First-in-Patient, Randomized, Double-Blind, Phase 1/2 Study in Systemic Lupus Erythematosus
Authors: Tanaka Yoshiya , Kumanogoh Atsushi , Atsumi Tatsuya , Ishii Tomonori , Tago Fumitoshi , Aoki Mari , Yamamuro Shintaro , Akira Shizuo
Published: April 2024

Objectives

To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response, and efficacy of E6742 in a phase 1/2 study in patients with systemic lupus erythematosus (SLE).

Methods

Two sequential cohorts of SLE patients were enrolled and randomized to 12 weeks of twice-daily treatment with E6742 (100 or 200 mg; n = 8 or 9) or placebo (n = 9).

Results

The proportion of patients with any treatment-emergent adverse events (TEAEs) was 58.8% in the E6742 group (37.5% for 100 mg; 77.8% for 200 mg) and 66.7% in the placebo group. No Common Terminology Criteria for Adverse Events ≥ Grade 3 TEAEs occurred. PK parameter levels were similar between SLE patients and healthy adults in previous phase 1 studies. The interferon gene signature (IGS) and levels of proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) after ex-vivo challenge with a Toll-like receptor 7/8 agonist were immediately decreased by E6742 treatment. Dose-dependent improvements in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response were observed at Week 12 in the E6742 (37.5% for 100 mg; 57.1% for 200 mg) and placebo (33.3%) groups. E6742 also had therapeutic effects on other symptoms, including skin inflammation, arthritis, and levels of anti-double-stranded DNA antibodies and complements.

Conclusions

E6742 had a favorable safety profile and was well tolerated, with marked IGS responses and sufficient efficacy signals in patients with SLE. These results provide the first clinical evidence to support E6742 in the treatment of SLE, and support larger, longer-term clinical trials.

Trial registration number

NCT05278663.

KEY MESSAGES

What is already known on this topic

Because of the limited efficacy and safety concerns of current drug therapies, unmet medical needs remain for many patients with systemic lupus erythematosus (SLE), necessitating new, more efficacious drugs.

There is strong evidence for the relationship between Toll-like receptor (TLR)7/8 and SLE pathophysiology, and two phase 1 clinical studies of E6742, a small molecular selective dual antagonist of TLR7/8, in healthy adults showed good tolerance without safety issues.

What this study adds

E6742 was well tolerated in this phase 1/2 clinical trial of patients with SLE, demonstrating a favorable safety profile and providing a markedly improved interferon gene signature and sufficient efficacy signals.

How this study might affect research, practice or policy

This study provides the first clinical evidence to suggest that E6742, as a first-in-class TLR7/8 inhibitor, may be beneficial for SLE.

The study outcomes also support larger, longer-term clinical trials of E6742.
Dopa responsiveness in Parkinson’s disease
Authors: Gandhi Sacha E , Nodehi Anahita , Lawton Michael A , Grosset Katherine A , Marshall Vicky , Ben-Shlomo Yoav , Grosset Donald G
Published: April 2024

Background

Dopaminergic responsiveness is a defining feature of Parkinson’s disease (PD). However, there is limited information on how this evolves over time.

Objectives

To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these.

Methods

We analyzed data from theParkinson’s Progression Markers Initiativeon repeated dopaminergic challenge tests (≥ 24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters.

Results

There were 1,525 dopaminergic challenge tests from 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer duration (51.1-74.3%). We identified 3 response groups: ‘Striking’ (n = 29, 8.7%); ‘Excellent’ (n = 110; 32.7%) and ‘Modest’ (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01).

Conclusion

Three distinct patterns of the dopaminergic response were observed. The proportion of PD cases with definite dopa responsiveness increased over time, so the initial treatment response may be an unreliable diagnostic aid.
Rationale and design of the Cancer Immunotherapy Evidence Living (CIEL) Library: A continuously updated clinical trial database of cancer immunotherapies
Authors: Boesen K , Hirt J , Düblin P , Läubli H , Kassenda B , Hemkens LG , Janiaud P
Published: April 2024

Background

Immunotherapies for cancers are being tested in large numbers of clinical trials. It is nearly impossible for clinicians and researchers to stay current with the evidence, and traditional systematic reviews and clinical guidelines are not suited to ensure a continued overview of all trials and their results. To address this problem, we have designed a free-to-use, and publicly available database of clinical trials that aims to be continuously updated, the Cancer Immunotherapy Evidence Living (CIEL) Library.

Methods

We aimed to include planned, ongoing, and completed interventional trials of immunotherapies for cancer, regardless of trial design (e.g., randomization, blinding, and type of comparator). We systematically searched PubMed (for published reports) andClinicalTrials.gov(for registered clinical trials). PubMed retrieved records were screened using the AI-assisted software ASReview and manually extracted and curated. We imported data fromClinicalTrials.govusing the Clinical Trials Transformation Initiative database which then requires further curation. The CIEL-Library is available and searchable via a web application (https://app.ciel-library.org/#/). It also contains the ‘Match My Patient’ feature, a patient-centered clinical decision support system, which can filter planned, ongoing or completed trials based on four patient characteristics (disease staging, previous treatments, performance status, and location). We piloted our database with one type of cancer immunotherapy, the tumor-infiltrating lymphocytes (TIL) transfer.

Conclusion

The CIEL-Library offers a blueprint for a dynamic evidence synthesis infrastructure providing an exhaustive collection of clinical trials with trial characteristics and results, which can be applied across different fields, specialties, and topics. The Match My Patient search function may be very useful to implement trial research into patient-centered care by helping to find a trial for enrolment of a patient or to find results for making decisions, for example, in tumor boards.

The main challenges to making a continuously updated database of clinical trials are the time and resources needed to populate it with curated and updated data. The CIEL-Library project illustrates the potential and the main limitations to designing such continuously updated trial databases that intent to be directly used in routine care.
A single episode of sexual reproduction can prevent population extinction under multiple stressors
Authors: Kawaguchi Yawako W. , Yamamichi Masato
Published: April 2024

Recent studies have shown that organisms can adapt to changing environments through rapid contemporary evolution. Although intraspecific genetic variation is necessary for rapid evolution to occur, little is known how genetic variation has been produced and maintained before rapid evolution. Here we show that a single episode of sexual reproduction can produce a large amount of intraspecific trait variation that allows population growth in degraded environments by laboratory experiments of a green alga,Closterium peracerosum–strigosum–littoralecomplex. We observed population dynamics of the alga under multiple stressors and confirmed that high salinity and low pH decreased population growth rates. By comparing parental and their hybrid F1populations, we observed larger variation in population growth rates of F1populations (i.e., transgressive segregation) when pH was low. Interestingly, even when parental populations had negative growth rates, some F1populations showed positive growth rates in severe environmental conditions due to the large variation in population growth. By utilizing the recently obtained genomic information of the alga, we found greater enrichment of genes with copy number variations in terms related to pH stress than those to salt stress in a gene ontology (GO) enrichment analysis. Our results suggest that recombination and variation in the number of gene copies might produce large genetic variation in the F1generation. This will be an important step toward a better understanding of evolutionary rescue, where rapid evolution prevents population extinction in changing environments.
CRISPR PERSIST-On enables heritable and fine-tunable human gene activation
Authors: Tak Y. Esther , Hsu Jonathan Y. , Shih Justine , Schultz Hayley T. , Nguyen Ivy T. , Lam Kin Chung , Pinello Luca , Keith Joung J.
Published: April 2024

Current technologies for upregulation of endogenous genes use targeted artificial transcriptional activators but stable gene activation requires persistent expression of these synthetic factors. Although general “hit-and-run” strategies exist for inducing long-term silencing of endogenous genes using targeted artificial transcriptional repressors, to our knowledge no equivalent approach for gene activation has been described to date. Here we show stable gene activation can be achieved by harnessing endogenous transcription factors (EndoTFs) that are normally expressed in human cells. Specifically, EndoTFs can be recruited to activate endogenous human genes of interest by using CRISPR-based gene editing to introduce EndoTF DNA binding motifs into a target gene promoter. This Precision Editing of Regulatory Sequences to Induce Stable Transcription-On (PERSIST-On) approach results in stable long-term gene activation, which we show is durable for at least five months. Using a high-throughput CRISPR prime editing pooled screening method, we also show that the magnitude of gene activation can be finely tuned either by using binding sites for different EndoTF or by introducing specific mutations within such sites. Our results delineate a generalizable framework for using PERSIST-On to induce heritable and fine-tunable gene activation in a hit-and-run fashion, thereby enabling a wide range of research and therapeutic applications that require long-term upregulation of a target gene.