bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities of the liver have big impacts on orthotopic liver transplantation
Authors: Chen Yongfeng , Li Wenzhong , Chen Guoyong , Zhou Shaotang
Published: October 2024

Background

Orthotopic rat liver transplantation (OLT) is widely used in basic research; normal liver anatomy and structures are attributable to its success while its deformities complicate to have a negative on OLT.

Methods

For tolerance induction project, we performed OLT from Lewis to Brown Norway (BN) rat as chronic rejection model and encountered two anatomical deformities of recipient rats: of 47 liver transplantations, accessory liver lobe occurred to 4 cases and bifurcations of liver outflow to 5 cases in BN rats.

Results

For the accessory liver lobe, we discontinued OLT for one case with a big accessory liver lobe; two rats died from pneumothorax upon separation; and succeed in one case with the small lobe. For two vein outflows of the liver, we succeeded in OLT due to its reconstruction in one case but the recipient died one week later, and succeeded in 1 case after one small orifice was sutured, we failed in 3 cases due to thrombosis following OLT. For 38 rats with normal livers, only 4 rats failed to survive LT. There were significant differences in OLT success (p<0.01)

Conclusion

Liver abnormal anatomy has negative impact on OLT, giving a clue to that pre-transplant comprehensive screening is significant and beneficial clinically.
Ligand-Receptor Interactions for Cell-Cell Communication Analysis in Rat, Chicken, Pig, and Monkey Single-Cell and Spatial Transcriptomics
Authors: Chen Sheng , Peng Yan , Zhang Xiaoling , Jiang Ting , Fang Binbin , Zhang Pengyue , Li Yanze , Ren Yonghong , Sun Yimin
Published: October 2024

Cell-cell communication is a frequently used analysis approach in single cell RNA and spatial transcriptomics, and many tools like CellPhoneDB, CellChat and stLearn have been developed. Ligand-receptor interactions are the core of cell-cell communication analysis. Since receptor-ligand and even protein-protein interactions were focus on humans and mice research, curated human and mouse receptor-ligand databases have been established, cell-cell interactions for these two species single-cell RNA sequencing data can be directly analyzed. However, for rats, chickens, pigs, monkeys, and other species, cell-cell interaction analysis is often implemented through orthologous gene mapping, due to the lack of curated ligand-receptor interaction databases for these species.

We collected cell-cell interaction data mainly from KEGG for rats, chickens, pigs, and monkeys, and extended the data from Reactome and IntAct. Then, by using CellChatV2 with our collected rat ligand-receptor interactions and CellChatV2’s own mouse data, respectively, we analyzed 10x Genomics rat public scRNA data, and found that 70 significantly ligand-receptor interactions from the mouse analysis result were also significantly in rats. We also obtained some chicken, pig, and monkey scRNA data from published literature, and analyzed cell-cell interactions using our collected ligand-receptor interactions for these species, and it was proved that our data is reliable and useful. Lastly, we have transformed the ligand-receptor interactions for rat, chicken, pig, and monkey species into the CellChatDB format, which enables swift and straightforward analysis of cell-cell communication in single-cell and spatial data of these four species.

All the ligand-receptor interaction datasets for rats, chickens, pigs, and monkeys, as well as the program codes, are available athttps://github.com/qingchen36/ligand-receptor. Using our program, one can rapidly obtain receptor-ligand interaction data for other species.
Optimisation of explant-specific isolation, culture, and micro-callus induction of sesame (Sesamum indicumL.) protoplasts
Authors: Debnath Anirban Jyoti , Basu Debabrata , Sikdar Samir Ranjan
Published: October 2024

The low yield of sesame (Sesamum indicumL.) compared to other oilseed crops hinders its successful commercialisation process. Sesame yield improvement using molecular-biotechnological tools involving gene manipulation is a better alternative than traditional breeding because it requires less time, effort, and labour. Protoplasts are plant cells devoid of the cell wall. Protoplast systems are deployed as versatile cell-based tools for tissue culture, genomics, transcriptomics, proteomics, metabolomics, and epigenetics studies leading to crop improvement. Inadequate reports of sesame protoplasts restrict its potential use in this crop. In the present study, we are reporting the successful isolation and purification of sesame protoplasts from four different sesame explants: hypocotyl, internode, leaf, and hypocotyl-derived callus using the one-step enzymatic digestion method. We have carefully optimised enzyme combinations, digestion durations, temperatures, and shaking speeds for every tested explant to obtain the highest protoplast yield and viability. Maximum yield (9.9 x 106protoplasts/gm fresh weight) and viability (92.1%) were achieved from callus explants. We purified isolated protoplasts by floating them over a 20% (w/v) sucrose solution. Among tested media, callus-derived protoplasts divided rapidly in Murashige and Skoog broth medium supplemented with 17.77 μM 6-benzylaminopurine (BAP) and 0.54 μM α-naphthalene acetic acid (NAA). In the same medium, protoplasts divided into the 2-cell stage after 2-3 days of culture and progressed to the micro-callus stage at 0.24 ± 0.05% frequency within 16-20 days of culture. Sesame protoplasts could be an excellent system for investigating potential avenues for biotechnological improvements of sesame including transient gene expression and CRISPR-based studies.
Visualizing nucleation, condensation and propagation of β-tubulin folding in chaperonin TRiC
Authors: Zhao Yanyan , Schmid Michael F. , Chiu Wah
Published: October 2024

The folding nucleus (FN) initiates protein folding and enables an efficient folding pathway. Here we directly visualize the tubulin FN consisting of a nonnative, partially assembled Rossmann fold, in the closed chamber of human chaperonin TRiC. Chaperonin TRiC interacts with non-natively folded secondary structural elements, stabilizing the nucleus for transition into its first native domain. Through progressive folding, the unfolded sequence goes through drastic spatial arrangement in the TRiC chamber to sample the conformational space, mediated by the highly dynamic CCT tails. The observed presence of individual nonnative secondary structures first in the nonnative FN and then around the incrementally folded native domains supports the hypothesis that tubulin folding in TRiC is a hierarchical process of nucleation, condensation and propagation in cooperation with TRiC subunits.
The long non-coding RNAFAM30Aregulates the Musashi2-RUNX1 axis and is required for LSC function in AML cells
Authors: Calvo Sánchez Jaime , Scott Mary T. , Varnava Athina , Alakhras Tala , Wedler Alice , Misiak Danny , Bley Nadine , Ihling Christian , Sinz Andrea , Keeshan Karen , Hüttelmaier Stefan , Vetrie David , Köhn Marcel
Published: October 2024

High expression of the long non-coding RNA (lncRNA)FAM30Ahas been previously associated with leukemic stem cell (LSC) activity and poor prognosis in both adult and paediatric acute myeloid leukaemia (AML) patients, yet it has not been functionally studied. This study provides the first cellular characterization ofFAM30Afocussing on an internal tandemly organised region, referred to asFAM30Arepeats.FAM30Alevels correlated with canonical AML LSC signatures andFAM30Adepletion decreased cell viability as well as increased sensitivity to chemotherapeutics. It also inhibited colony formation, promoted granulocytic differentiation and abrogated leukemic engraftment in murine bone marrowin vivo. Overexpression ofFAM30Arepeats in this setting enhanced stemness, proliferation, chemoresistance, and engraftment thus highlighting the biological relevance of this region for LSC biology. On the molecular level,FAM30Arepeats interact with the pro-LSC regulator Musashi-2 (MSI2), positively influencing expression of its targets including RUNX1 isoforms. We herein uncover that thisFAM30A-MSI2-RUNX1 regulatory loop is of potential relevance for LSC maintenance in AML. These findings provide valuable insights intoFAM30A's cellular role and highlight its targeting potential for eliminating LSCs and improving treatment outcomes in AML patients.
Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges
Authors: Tong Xinran , Remsik Jan , Brook Jeanette , Petrova Boryana , Xu Lele , Li Min Jun , Snyder Jenna , Chabot Kiana , Estrera Rachel , Osei-Gyening Isaiah , Nobre Ana Rita , Wang Helen , Osman Ahmed M , Wong Alan Y.L. , Sidharta Mega , Piedrafita-Ortiz Sofia , Manoranjan Branavan , Zhou Ting , Murali Rajmohan , Hamard Pierre-Jacques , Koche Richard , He Ye , Kanarek Naama , Boire Adrienne
Published: October 2024

Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC-and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with RA induced expression of transcripts encodingde novofatty acid synthesis pathway enzymesin vitro.In vivo, while deletion ofStra6did not alter cancer cell leptomeningeal growth, knockout ofRxra/b/ginterrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby metastatic cancer cells awake locally-generated developmental cues for metabolically reprograming, suggesting novel therapeutic approaches.
The role of theADRB2Thr164Ile variant in lung function determination, plasma proteome variability and other phenotypes in UK Biobank
Authors: Fawcett Katherine A , Hall Robert J , Packer Richard , Coley Kayesha , Shrine Nick , Wain Louise V , Tobin Martin D , Hall Ian P
Published: October 2024

Introduction

The effect of coding polymorphisms of the beta-2 adrenergic receptor gene (ADRB2) on functional properties of the receptor is well-established. We recently reported a genome-wide significant association between Thr164Ile and lung function, but the contribution of this variant to other traits remains unclear.

Methods

To identify pleiotropic effects ofADRB2Thr164Ile and other coding variants, we performed respiratory-focused and phenome-wide association studies in UK Biobank. In addition, we used available Olink proteomic data to characterise enriched pathways and upstream regulators of proteins associated withADRB2polymorphisms.

Results

The minor allele of Thr164Ile was associated with reduced lung function, but not COPD or asthma defined using self-report and diagnostic codes in healthcare records. It was also associated with non-respiratory traits including increased eosinophil counts and blood lipid measurements, including increased cholesterol, reduced triglycerides and reduced apolipoprotein A. Proteins associated with Thr164Ile (P-value≤0.01) were enriched for various pathways, with the eosinophil-raising allele associated with reduced neutrophil degranulation, immunoregulatory interactions between a Lymphoid and a non-Lymphoid cells, TNF binding and DAP12 interactions, as well as activation of lipid metabolism pathways, including FXR/RXR activation and LXR/RXR activation. A gene-based analysis of rare, non-synonymousADRB2variants, identified a novel association with non-rheumatic pulmonary valve disorders, but no association with lung function.

Discussion

In conclusion, the lung function-lowering allele of Thr164Ile is associated with traits and proteins indicative of a role in immune and lipid metabolism pathways, but not COPD or asthma. In contrast,ADRB2rare coding variants are not associated with lung function.
Validity, Reliability, and Framing Effects in Equity-Efficiency Trade-Off Studies: A Systematic Review
Authors: Chechulina Victoria , Chu Andrew , Lam Quang Hung , Kabir-Bahk Camryn , Ali Shehzad
Published: October 2024

Objectives

Health system resources are limited, and decision makers often need to make trade-offs between equity and efficiency. Such trade-offs are guided by public values that are elicited using choice experiments. There is no standard approach to elicit equity-efficiency trade-offs. Previous studies have found significant variability in public values, raising concerns about the robustness of trade-off experiments. The objective of this systematic review was to determine whether and how equity-efficiency trade-off studies consider validity, reliability and framing effects.

Methods

We searched Medline, EMBASE, and Web of Science in January 2024 for health-related equity-efficiency trade-off studies. Two reviewers independently screened titles and abstracts, followed by full-text review, data extraction, and quality assessment.

Results

115 equity-efficiency trade-off studies were identified, of which 29 studies (25.2%) investigated validity, reliability, and/or framing effects. 14 (12.2%) studies assessed validity, 9 (7.8%) studies assessed reliability, and 10 (8.7%) assessed framing or cognitive effects. Validity was most frequently assessed by comparing results to hypothesized expectations, while reliability was commonly assessed by providing a repeated test or questionnaire. Framing and cognitive effects were assessed by varying question order or changing the wording or framing of the scenario. 19 of 23 studies reported high or acceptable validity or reliability, and 5 of 10 studies found no significant framing or cognitive effects.

Conclusion

This systematic review highlights the need to consider robustness of elicited values in choice experiments. It will also guide future choice experiments that aim to estimate inequity aversion.
The Humanitarian-Development Nexus and Sexual and Reproductive Health Interventions in Fragile Settings: A Scoping Review
Authors: Qaddour Amany , Tappis Hannah , Lazieh Stefany , Ward Ava , Spiegel Paul
Published: October 2024

The concurrent need for both humanitarian and development assistance in fragile settings and protracted emergencies has been termed the humanitarian-development nexus (HDN) or the humanitarian-development-peace nexus (HDpN). We undertook a scoping review on the operationalization of the HDpN for sexual, reproductive, maternal, newborn, child, and adolescent health interventions in fragile settings. We screened 2,183 publications, of which 29 peer-reviewed and 16 grey literature publications met inclusion criteria. No included studies focused on peace aspects within the HDpN and very few focused on child and adolescent health. Publications by humanitarian authors often classified maternal and newborn health as a component of sexual and reproductive health (SRH). Data extraction and analysis focused on three overarching themes: SRH prioritization across the HDN, the transition between minimum and comprehensive services, and health systems strengthening. This review provides concrete guidance on how to operationalize the HDN for SRH interventions in fragile settings. Expansion of SRH preparedness measures is necessary given the current trajectory of the climate emergency and other destabilizing events. The ability to flexibly transition between minimum and comprehensive services is important for maintaining service continuity in crisis-affected settings. COVID-19 proved to be a significant disruptor of SRH services, and a key inflection point in the collaboration between humanitarian and development practitioners. The use of task-shifting, decentralization, and telemedicine were approaches that may be adopted to maintain service delivery according to different contexts. Lastly, strengthening health systems was identified as essential across the HDN. With more crises extending for years, the wider literature has emphasized the necessity of health systems strengthening for reaching the Sustainable Development Goals, including in fragile settings.
Pathologic subtyping of Alzheimer’s disease brain tissue reveals disease heterogeneity
Authors: Lam Tiffany G. , Ross Sophie K. , Ciener Benjamin , Xiao Harrison , Flaherty Delaney , Lee Annie J. , Dugger Brittany N. , Reddy Hasini , Teich Andrew F.
Published: October 2024

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer’s Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes. Pathologic clustering suggests 8 subtypes within this cohort, and further analysis reveals that the previously described continuum from hippocampal predominant to hippocampal sparing is well represented in our data. Small vessel disease is overall highest in a cluster with a low hippocampal/cortical tau ratio, and across all clusters small vessel disease segregates separately from Lewy body disease. Two AD clusters are identified with extensive Lewy bodies outside amygdala (one with a high hippocampal/cortical tau ratio and one with a low ratio), and we find an inverse relationship between cortical tau and Lewy body pathology across these two clusters. Finally, we find that brains from persons of Hispanic descent have significantly more AD pathology in multiple neuroanatomic areas. We find that Hispanic ethnicity is not uniformly distributed across clusters, and this is particularly pronounced in clusters with significant Lewy body pathology, where Hispanic donors are only found in a cluster with a low hippocampal/cortical tau ratio. In summary, our analysis of recorded pathologic data across two decades of banked brains reveals new relationships in the patterns of AD-related proteinopathy, co-pathology, and ethnicity, and highlights the utility of pathologic subtyping to classify AD pathology.

Abbreviated summary

Multiple groups have shown that what is currently thought of as "Alzheimer’s Disease" (AD) may be usefully viewed as several related disease subtypes. Here, we utilize two decades of banked cases to demonstrate how co-pathology and ethnicity intersect with one of the most widely used methods of pathologic subtyping.
Comparison of immunogenicity of adjuvanted and high dose influenza vaccination in long-term care facility residents
Authors: Didion Elise M. , Kass Joseph D. , Wilk Dennis J. , Buss Emily , Frischmann Sarah-Michelle , Rubeck Sabina , Banks Richard , Wilson Brigid M. , Gravenstein Stefan , Canaday David H.
Published: October 2024

Background

The CDC recommends the more immunogenic adjuvanted and high-dose flu vaccines over standard-dose, non-adjuvanted vaccines for individuals above 65 years old. The current study compares adjuvanted trivalent inactivated flu vaccine (aTIV, FLUAD) versus high-dose flu vaccine (HD-IIV3, FLUZONE HD) to determine if they met non-inferiority standards for older long-term care facility (LTCF) residents.

Methods

We collected blood from long-term care facility residents participating in a randomized 1:1 active control trial comparing MF59C.1 adjuvanted trivalent inactivated flu vaccine, aTIV versus HD-IIV3 over the course of two flu seasons, 2018-2019 and 2019-2020 (Trial,NCT03694808). We assessed humoral immunity at set time points via hemagglutinin inhibition assays (HAI) and anti-neuraminidase (enzyme-linked lectin assays (ELLA)). The recombinant influenza vaccine (RIV, Flublok) was assessed similarly in year two for a small number of participants who were carried over from year 1 (n=32).

Results

We enrolled 387 volunteers and administered either aTIV (n=194), HD-IIV3 (n=193) over the course of the 2018-2019 and 2019-2020 flu seasons. Among those enrolled and randomized in year one, a subset were administered RIV and studied in year two (n = 32). At 28 days post-vaccination, aTIV exhibited non-inferiority to HD-IIV3 for HAI for both H1N1 and H3N2 strains (GMT ratios (95% CI) for HD-IIV3/aTIV of 1.03(0.76, 1.4) and 1.04(0.73, 1.48), respectively; both 95% CI upper bounds < 1.5 to meet non-inferiority criteria) but not for Influenza B (GMT ratio (95% CI) = 1.21 (0.91, 1.61)). Non-inferiority criteria for HAI seroconversion were not met for any of the three strains. Applying the same non-inferiority criteria to neuraminidase inhibition (NI), both day 28 titer and seroconversion in aTIV were non-inferior to HD-IIV3 for H1N1 and H3N2 strains.

Conclusions

Both aTIV and HD-IIV3 elicited similar immune responses with robust antibody responses. For the primary outcome, aTIV is non-inferior to HD-IIV3 for HAI titer of H1N1 and H3N2 but failed to meet non-inferiority criteria for Influenza B and seroconversion for all assessed strains. For the secondary outcome, aTIV was non-inferior to HD-IIV3 for both titer and seroconversion of anti-neuraminidase for both H1N1 and H3N2.
Machine learning to classify left ventricular hypertrophy using ECG feature extraction by variational autoencoder
Authors: Gupta Amulya , Harvey Christopher J. , DeBauge Ashley , Shomaji Sumaiya , Yao Zijun , Noheria Amit
Published: October 2024

Background

Traditional ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield. Machine learning (ML) can improve ECG classification.

Methods

ECG summary features (rate, intervals, axis), R-wave, S-wave and overall-QRS amplitudes, and QRS/QRST voltage-time integrals (VTIs) were extracted from 12-lead, vectorcardiographic X-Y-Z-lead, and root-mean-square (3D) representative-beat ECGs. Latent features were extracted by variational autoencoder from X-Y-Z and 3D representative-beat ECGs. Logistic regression, random forest, light gradient boosted machine (LGBM), residual network (ResNet) and multilayer perceptron network (MLP) models using ECG features and sex, and a convolutional neural network (CNN) using ECG signals, were trained to predict LVH (left ventricular mass indexed in women >95 g/m², men >115 g/m²) on 225,333 adult ECG-echocardiogram (within 45 days) pairs. AUROCs for LVH classification were obtained in a separate test set for individual ECG variables, traditional criteria and ML models.

Results

In the test set (n=25,263), AUROC for LVH classification was higher for ML models using ECG features (LGBM 0.790, MLP 0.789, ResNet 0.788) as compared to the best individual variable (VTIQRS-3D0.677), the best traditional criterion (Cornell voltage-duration product 0.647) and CNN using ECG signal (0.767). Among patients without LVH who had a follow-up echocardiogram >1 (closest to 5) years later, LGBM false positives, compared to true negatives, had a 2.63 (95% CI 2.01, 3.45)-fold higher risk for developing LVH (p<0.0001).

Conclusions

ML models are superior to traditional ECG criteria to classify—and predict future—LVH. Models trained on extracted ECG features, including variational autoencoder latent variables, outperformed CNN directly trained on ECG signal.
LABOR DURATION IS DEFINED BY THE TIME OF DAY OF LABOR INDUCTION
Authors: Cataldo Kylie , Long Robert , Olomnu Isoken , Cortese Rene , Hoffmann Hanne M.
Published: October 2024

BACKGROUND

Spontaneous labor and birth peak during the late evening and early morning hours, indicating an endogenous rhythm in labor onset and birth. We hypothesize that the time-of-day of labor induction will define labor duration and the risk of cesarian section.

METHODS

In a retrospective study of pregnant women who were induced for labor (n =3,688), time-of- day of labor induction was studied across maternal phenotypes. Survival analysis and Cox Proportional Hazards model were used to identify differences in time-to-birth as a result of inducing labor at a specific time-of-day.

RESULTS

Labor induction was circadian (p<0.05, Lomb-Scargle test), with a gradual lengthening in labor duration when labor induction was initiated later in the day, peaking at 23:00 hours (average labor duration of 20.72 hours) as compared to induction at 5:00 hours (average labor duration of 14.74 hours, p<0.01, Kruskal-Wallis test). The optimal time-of-day of labor induction was conditioned by maternal phenotype with significant differences in probability of giving birth as a result of the time-of-day labor was induced for nulliparous obese (p<0.05, Two-way ANOVA), and parous obese women (p<0.05).

CONCLUSIONS

Labor duration in response to induction is circadian, with the shortest labor duration when induced during early morning hours. The optimal time-of-day of labor induction is conditioned by maternal phenotype and should be considered as a labor management practice.
The Use of Machine Learning in Occupational Risk Communication for Healthcare Workers – Protocol for scoping review
Authors: de Oliveira Gabriela Laudares Albuquerque , Bonow Clarice Alves , de Oliveira Castellano Rodrigues Itiberê , Geraldo Amanda Xavier
Published: October 2024

Introduction

With the development of technology, the use of machine learning (ML), a branch of computer science that aims to transform computers into decision-making agents through algorithms, has grown exponentially. This protocol arises from the need to explore the best practices for applying ML in the communication and management of occupational risks for healthcare workers.

Methods and analysis

This scoping review protocol1details a search to be conducted in the academic databases Public Medical Literature Analysis and Retrieval System Online (PUBMED), through the Virtual Health Library (BVS): Medical Literature Analysis and Retrieval System (MEDLINE), Latin American and Caribbean Literature in Health Sciences (LILACS), West Pacific (WPRIM), Nursing Database (BDENF) and Scientific Electronic Library Online (SciELO), SCOPUS, Web of Science, IEEE Xplore Digital Library and Excerpta Medica Database (EMBASE). This scoping review protocol outlines the objectives, methods, and timeline for a review that will explore and map the existing scientific evidence and knowledge on the use of machine learning (ML) in risk communication for healthcare workers. This protocol follows the PRISMA-ScR2and JBI guidelines3for conducting scoping reviews. The guiding question of the review is: How is machine learning used in risk communication for healthcare workers? The search will use PCC (Population, Concept, Context) terms and the specific descriptors defined by each database. The narrative synthesis will describe the main themes and findings of the review.

The results of this scoping review will be disseminated through publication in an international peer-reviewed scientific journal.

Ethics and dissemination

Ethical approval is not required; data will rely on published articles. Findings will be published open access in an international peer-reviewed journal.

Strengths and limitations of this study

Strengths

The study allows for comprehensive mapping of existing evidence on ML in occupational risk communication.

The methodology follows PRISMA-ScR and JBI guidelines, ensuring transparency and replicability.

The research employs a broad search strategy across multiple databases to capture relevant studies.

Limitations

The accuracy of ML models is dependent on the quality of the data used.

The implementation of ML in healthcare requires careful evaluation of ethical, legal, and privacy issues.

Registration details OSF Registries:The protocol for this review was registered in the Open Science Framework under DOI 10.17605/OSF.IO/92SK4 (available athttps://osf.io/92SK4).
3D super-resolution imaging of PSD95 reveals an abundance of diffuse protein supercomplexes in the mouse brain
Authors: Daly Sam , Bulovaite Edita , Handa Anoushka , Morris Katie , Muresan Leila , Adams Candace , Kaizuka Takeshi , Kitching Alexandre , Spark Alexander , Chant Gregory , O’Holleran Kevin , Grant Seth G. N. , Horrocks Mathew H. , Lee Steven F.
Published: October 2024

PSD95 is an abundant scaffolding protein that assembles multiprotein complexes controlling synaptic physiology and behavior. Confocal microscopy has previously shown that PSD95 is enriched in the postsynaptic terminals of excitatory synapses and 2D super-resolution microscopy further revealed that it forms nanoclusters. In this study, we utilized 3D super-resolution microscopy to examine the nanoarchitecture of PSD95 in the mouse brain, characterizing over 8 million molecules. While we were able to identify structural subtypes previously reported, imaging in 3D allowed us to classify these with higher accuracy. Furthermore, 3D super-resolution microscopy enabled the quantification of protein levels, revealing an abundance of PSD95 molecules existed outside of synapses as a diffuse population of supercomplexes, containing multiple copies of PSD95. Further analysis of the supercomplexes containing two units identified two populations: one that had PSD95 molecules separated by 39 ± 2 nm, and a second with a separation of 94 ± 27 nm. These results suggest that PSD95 supercomplexes containing multiple protein copies assemble outside the synapse and then integrate into the synapse to form a supramolecular nanocluster architecture.
Individual G-quadruplex targeting with ligand-functionalized CRISPR-Cas9 uncovers transcriptional-dependent functional responses
Authors: Nuccio Sabrina Pia , Cadoni Enrico , Nikoloudaki Roxani , Galli Silvia , Ler An-Jie , Maher Thomas E. , Fan Ella , Liu Ling Sum , Fullenkamp Christopher R. , Schneekloth John S. , Di Antonio Marco
Published: October 2024

The development of selective ligands to target DNA G-quadruplexes (G4s) has been pivotal in revealing their role in transcriptional regulation. However, most of the ligands described to date lack intra-G4 selectivity, severely limiting their potential for uncovering the biological function of individual G4s across the genome. To overcome these limitations, we developed ATENA (Approach to Target Exact Nucleic Acid alternative structures). ATENA relies on the chemical modification of established G4-ligands to enable their conjugation onto a catalytically inactive Cas9 protein (dCas9) using HaloTag, allowing for the targeting of individual G4s in living cells. We have systematically screened the length of the PEG-linkers connecting the G4-ligands to the HaloTag and sgRNA sequences to attain optimal G4 engagement bothin vitroand in cells. Using optimized conditions, we leveraged ATENA to demonstrate how the selective targeting of the well-studied G4 in the promoter of the oncogenec-MYCsuppresses its transcription exclusively from the P1 promoter. We also show that positioning ligands in the proximity of regulatory elements suppressesc-MYCtranscription in a G4-independent manner, highlighting the importance of appropriate design to measure genuine G4-mediated transcriptional changes. We also demonstrate that selective targeting of a G4 in thePVT1promoter can either stimulate or repress its transcription depending on the type of G4-ligand used, indicating that functional responses associated with G4-stabilization can highly depend on the type of ligand used. We further harnessed ATENA to study transcriptional perturbation associated with cell-specific G4s, revealing that the functional responses associated with these structures are tightly linked with the expression levels of the targeted gene. Our study provides critical insights into G4-based therapeutic design, offering an innovative platform to investigate G4 biology with high precision.
Collectiveβ-lactam resistance inEscherichia colidue toβ-lactamase release upon cell death
Authors: Gross Rotem , Mungan Muhittin , Das Suman G. , Yüksel Melih , Maier Berenike , Bollenbach Tobias , Krug Joachim , de Visser J. Arjan G.M.
Published: October 2024

Collective antibiotic resistance occurs when populations of bacteria survive antibiotic treatments that are lethal to individual bacteria, which affects the efficacy of drug therapies. Several mechanisms may lead to collective resistance, including the production of drug-degrading enzymes. Here, we integrate experiments with mathematical modeling to understand the collective survival ofEscherichia colichallenged with cefotaxime. We observe complex dynamics, involving initial biomass growth due to filamentation, followed by decline and subsequently growth recovery. We show that production of AmpC, a chromosomalβ-lactamase, is responsible for cefotaxime degradation, allowing the resumption of cell division in surviving filaments. Our model suggests that the release of AmpC via cell lysis accelerates antibiotic clearance, and does so particularly in strains with low cell-wall permeability that privatize periplasmic cefotaxime hydrolysis. Our findings support the hypothesis of enhanced survival ofβ-lactamase-producing bacterial populations via altruistic cell death.
The 3D point spread function can be autoencoded in latent space
Authors: Truedson Axel , Gras Konrad , Elf Johan
Published: October 2024

The 3D point spread function of a fluorescence emitter in a living cell is often different from that of the z-stack of bead images typically used as a reference. Here we show that the location in z of a fluorescent emitter can be directly accessed in the latent space of an autoencoder trained on the sample images without z-reference data. The corresponding decoding network represents an accurate point spread function.
Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder
Authors: Ghoochani Ali , Heiby Julia C. , Rawat Eshaan S. , Medoh Uche N. , Di Fraia Domenico , Dong Wentao , Gastou Marc , Nyame Kwamina , Laqtom Nouf N. , Gomez-Ospina Natalia , Ori Alessandro , Abu-Remaileh Monther
Published: October 2024

Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.
Shaping the mechanical properties of a gelatin hydrogel interface via amination
Authors: Adorno Génesis Ríos , Timmer Kyle B. , Chang Raul A. Sun Han , Shi Jiachun , Rogers Simon A. , Harley Brendan A. C.
Published: October 2024

Injuries to musculoskeletal interfaces, such as the tendon-to-bone insertion of the rotator cuff, present significant physiological and clinical challenges for repair due to complex gradients of structure, composition, and cellularity. Advances in interface tissue engineering require stratified biomaterials able to both provide local instructive signals to support multiple tissue phenotypes while also reducing the risk of strain concentrations and failure at the transition between dissimilar materials. Here, we describe adaptation of a thiolated gelatin (Gel-SH) hydrogel via selective amination of carboxylic acid subunits on the gelatin backbone. The magnitude and kinetics of HRP-mediated primary crosslinking and carbodiimide-mediated secondary crosslinking reactions can be tuned through amination and thiolation of carboxylic acid subunits on the gelatin backbone. We also show that a stratified biomaterial comprised of mineralized (bone-mimetic) and non-mineralized (tendon-mimetic) collagen scaffold compartments linked by an aminated Gel-SH hydrogel demonstrate improved mechanical performance and reduced strain concentrations. Together, these results highlight significant mechanical advantages that can be derived from modifying the gelatin macromer via controlled amination and thiolation and suggest an avenue for tuning the mechanical performance of hydrogel interfaces within stratified biomaterials.
Immune cells promote paralytic disease in mice infected with enterovirus D68
Authors: Woods Acevedo Mikal A. , Lan Jie , Maya Sarah , Jones Jennifer E. , Williams John V. , Freeman Megan Culler , Dermody Terence S.
Published: October 2024

Enterovirus D68 (EV-D68) is associated with acute flaccid myelitis (AFM), a poliomyelitis-like illness causing paralysis in young children. However, mechanisms of paralysis are unclear, and antiviral therapies are lacking. To better understand EV-D68 disease, we inoculated newborn mice intracranially to assess viral tropism, virulence, and immune responses. Wild-type (WT) mice inoculated intracranially with a neurovirulent strain of EV-D68 showed infection of spinal cord neurons and developed paralysis. Spinal tissue from infected mice revealed increased levels of chemokines, inflammatory monocytes, macrophages, and T cells relative to controls, suggesting that immune cell infiltration influences pathogenesis. To define the contribution of cytokine-mediated immune cell recruitment to disease, we inoculated mice lacking CCR2, a receptor for several EV-D68-upregulated cytokines, or RAG1, which is required for lymphocyte maturation. WT,Ccr2-/-, andRag1-/-mice had comparable viral titers in spinal tissue. However,Ccr2-/-andRag1-/-mice had significantly less paralysis relative to WT mice. Consistent with impaired T cell recruitment to sites of infection inCcr2-/-andRag1-/-mice, antibody-mediated depletion of CD4+or CD8+T cells from WT mice diminished paralysis. These results indicate that immune cell recruitment to the spinal cord promotes EV-D68-associated paralysis and illuminate new targets for therapeutic intervention.

Graphical Abstract
Theoretical framework for the difference of two negative binomial distributions and its application in comparative analysis of sequencing data
Authors: Petrany Alicia , Chen Ruoyu , Zhang Shaoqiang , Chen Yong
Published: October 2024

High-throughput sequencing (HTS) technologies have been instrumental in investigating biological questions at the bulk and single-cell levels. Comparative analysis of two HTS data sets often relies on testing the statistical significance for the difference of two negative binomial distributions (DOTNB). Although negative binomial distributions are well studied, the theoretical results for DOTNB remain largely unexplored. Here, we derive basic analytical results for DOTNB and examine its asymptotic properties. As a state-of-the-art application of DOTNB, we introduce DEGage, a computational method for detecting differentially expressed genes (DEGs) in scRNA-seq data. DEGage calculates the mean of the sample-wise differences of gene expression levels as the test statistic and determines significant differential expression by computing theP-value with DOTNB. Extensive validation using simulated and real scRNA-seq data sets demonstrates that DEGage outperforms five popular DEG analysis tools: DEGseq2, DEsingle, edgeR, Monocle3, and scDD. DEGage is robust against high dropout levels and exhibits superior sensitivity when applied to balanced and imbalanced data sets, even with small sample sizes. We utilize DEGage to analyze prostate cancer scRNA-seq data sets and identify marker genes for 17 cell types. Furthermore, we apply DEGage to scRNA-seq data sets of mouse neurons with and without fear memory and reveal eight potential memory-related genes overlooked in previous analyses. The theoretical results and supporting software for DOTNB can be widely applied to comparative analyses of dispersed count data in HTS and broad research questions.
Detecting m6A RNA modification from nanopore sequencing using a semisupervised learning framework
Authors: Teng Haotian , Stoiber Marcus , Bar-Joseph Ziv , Kingsford Carl
Published: October 2024

Direct nanopore-based RNA sequencing can be used to detect posttranscriptional base modifications, such as N6-methyladenosine (m6A) methylation, based on the electric current signals produced by the distinct chemical structures of modified bases. A key challenge is the scarcity of adequate training data with known methylation modifications. We present Xron, a hybrid encoder–decoder framework that delivers a direct methylation-distinguishing basecaller by training on synthetic RNA data and immunoprecipitation (IP)-based experimental data in two steps. First, we generate data with more diverse modification combinations through in silico cross-linking. Second, we use this data set to train an end-to-end neural network basecaller followed by fine-tuning on IP-based experimental data with label smoothing. The trained neural network basecaller outperforms existing methylation detection methods on both read-level and site-level prediction scores. Xron is a standalone, end-to-end m6A-distinguishing basecaller capable of detecting methylated bases directly from raw sequencing signals, enabling de novo methylome assembly.
Digitization and subduction of
SU(N)
gauge theories
Authors: Assi Benoît , Lamm Henry
Published: October 2024

The simulation of lattice gauge theories on quantum computers necessitates digitizing gauge fields. One approach involves substituting the continuous gauge group with a discrete subgroup, but the implications of this approximation still need to be clarified. To gain insights, we investigate the subduction of SU(2) and SU(3) to discrete crystal-like subgroups. Using classical lattice calculations, we show that subduction offers valuable information based on subduced direct sums, helping us identify additional terms to incorporate into the lattice action that can mitigate the effects of digitization. Furthermore, we compute the static potentials of all irreducible representations of Σ(360×3) at a fixed lattice spacing. Our results reveal a percent-level agreement with the Casimir scaling of SU(3) for irreducible representations that subduce to a single Σ(360×3) irreducible representation. This provides a diagnostic measure of approximation quality, as some irreducible representations closely match the expected results while others exhibit significant deviations.

Published by the American Physical Society
2024
Constraints on dark matter from dynamical heating of stars in ultrafaint dwarfs. I. MACHOs and primordial black holes
Authors: Graham Peter W. , Ramani Harikrishnan
Published: October 2024

We place limits on dark matter made up of compact objects significantly heavier than a solar mass, such as MACHOs or primordial black holes (PBHs). In galaxies, the gas of such objects is generally hotter than the gas of stars and will thus heat the gas of stars even through purely gravitational interactions. Ultrafaint dwarf galaxies (UFDs) maximize this effect. Observations of the half-light radius in UFDs thus place limits on MACHO dark matter. We build upon previous constraints with an improved heating rate calculation including both direct and tidal heating, and consideration of the heavier mass range above 104M⊙. Additionally we find that MACHOs may lose energy and migrate in to the center of the UFD, increasing the heat transfer to the stars. UFDs can constrain MACHO dark matter with masses between about 10M⊙ and 108M⊙ and these are the strongest constraints over most of this range.

Published by the American Physical Society
2024
Embedding space approach to Jackiw-Teitelboim gravity
Authors: Pinzul A. , Stern A. , Xu Chuang
Published: October 2024

We present a coordinate-free background space construction of Euclidean Jackiw-Teitelboim gravity. It is written as a gauge theory obtained from the Killing vectors and conformal Killing vectors of a hyperboloid embedded in a three-dimensional background. A novel feature of the gauge theory is that vanishing field strength does not necessarily imply that the gauge potentials (written in the embedding space) are pure gauges, not even locally. On the other hand, the projection of the potentials along the hyperboloid are pure gauges, as is the case in the standard approach. As is usual, metric tensors are dynamically generated from the classical solutions of the theory, which here do not rely on coordinate charts on the two-dimensional surface. We find a special class of solutions whereby the derived metric tensor on the surface is the induced metric from the background space. The gauge theory construction given here has a natural generalization to a noncommutative space, which does not require the use of coordinates, symbols, or a star product.

Published by the American Physical Society
2024
Assessment of knowledge integration in student learning of galvanic cell: An interdisciplinary approach connecting physics and chemistry
Authors: Ye Dewei , Qian Jiali , Xu Wangyi , Lu Yuyang , Wang Shuli , Xiao Longhai , Bao Lei
Published: October 2024

The galvanic cell is a typical interdisciplinary topic, which is primarily taught in chemistry but its underpinning is closely related to physics. Student learning in galvanic cell has been extensively studied in chemistry education, which has revealed a large number of misconceptions that are difficult to change through traditional instruction. A source of the learning difficulties is that most students lack an explanatory framework to integrate the many complex phenomena and processes into a coherent knowledge system. As a result, students often rely on memorization of terms, laws, and equations in solving problems but without a meaningful understanding of their reasoning. To address the deficit in learning, this study aims to help students develop an explanatory framework for supporting an integrated knowledge structure. Specifically, a conceptual framework model for galvanic cell is developed based on the central idea from physics, which is used as the core concept for mechanistic explanations of the related chemistry concepts. Guided by the conceptual framework, an instrument is developed to assess the knowledge integration in student learning of galvanic cell. A combination of qualitative and quantitative measures was used to assess the levels of knowledge integration in learning galvanic cell with a large number of Chinese high school and college students. The assessment results show that the conceptual framework model can effectively represent the knowledge structures of students at different levels of knowledge integration. The galvanic cell conceptual framework and assessment results can provide useful resources for teachers to develop instruction for promoting knowledge integration.

Published by the American Physical Society
2024
Moving impedance profiles make one-way, spectrum-reshaping mirrors
Authors: Li Mingjie , Horsley S. A. R.
Published: October 2024

We find a set of exact solutions to Maxwell's equations in spacetime-varying materials, where the refractive index is constant, while the impedance exhibits effective motion, i.e., it is a function of x−vt. We find that waves copropagating with the modulation are not reflected within the material, while counterpropagating waves are continually reflected by the changing impedance. For a finite section of such a material, we find analogs of transmission resonances, where specially shaped eigenpulses enter without reflection. We also find that there is a strong asymmetry in reflection from the medium when the impedance modulation is small but rapid, the material reflecting strongly from one side and negligibly from the other. Unlike stationary media, the spectrum of the reflected wave can be significantly different from the incident one.

Published by the American Physical Society
2024