The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway.

The twenty-three Fanconi anemia (FA) proteins cooperate in the FA/BRCA pathway to repair DNA interstrand cross-links (ICLs). The cell division cycle and apoptosis regulator 1 (CCAR1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression in human cells. Interestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing. Loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the EF hand domain, is required for interaction with the U2AF heterodimer of the spliceosome and for excision of the poison exon. Taken together, CCAR1 is a splicing modulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular pathways.

Deconwolf enables high-performance deconvolution of widefield fluorescence microscopy images.

Microscopy-based spatially resolved omic methods are transforming the life sciences. However, these methods rely on high numerical aperture objectives and cannot resolve crowded molecular targets, limiting the amount of extractable biological information. To overcome these limitations, here we develop Deconwolf, an open-source, user-friendly software for high-performance deconvolution of widefield fluorescence microscopy images, which efficiently runs on laptop computers. Deconwolf enables accurate quantification of crowded diffraction limited fluorescence dots in DNA and RNA fluorescence in situ hybridization images and allows robust detection of individual transcripts in tissue sections imaged with ×20 air objectives. Deconvolution of in situ spatial transcriptomics images with Deconwolf increased the number of transcripts identified more than threefold, while the application of Deconwolf to images obtained by fluorescence in situ sequencing of barcoded Oligopaint probes drastically improved chromosome tracing. Deconwolf greatly facilitates the use of deconvolution in many bioimaging applications.

Metasurface of Strongly Coupled Excitons and Nanoplasmonic Arrays.

Metasurfaces allow light to be manipulated at the nanoscale. Integrating metasurfaces with transition metal dichalcogenide monolayers provides additional functionality to ultrathin optics, including tunable optical properties with enhanced light-matter interactions. In this work, we demonstrate the realization of a polaritonic metasurface utilizing the sizable light-matter coupling of excitons in monolayer WSe2 and the collective lattice resonances of nanoplasmonic gold arrays. We developed a novel fabrication method to integrate gold nanodisk arrays in hexagonal boron nitride and thus simultaneously ensure spectrally narrow exciton transitions and their immediate proximity to the near-field of array surface lattice resonances. In the regime of strong light-matter coupling, the resulting van der Waals metasurface exhibits all key characteristics of lattice polaritons, with a directional and linearly polarized far-field emission profile dictated by the underlying nanoplasmonic lattice. Our work can be straightforwardly adapted to other lattice geometries, establishing structured van der Waals metasurfaces as means to engineer polaritonic lattices.

Informing the Need for a SARS-CoV-2 Booster Based Upon the Immune Responses among Young Healthy Adults to Variants Circulating in Late 2023.

BACKGROUND: COVID-19 remains a global public health challenge due to new immune-evasive SARS-CoV-2 variants and heterogeneous immunity. METHODS: In this cross-sectional study, we evaluated the adaptive immune responses in U.S. active-duty personnel who completed a COVID-19 primary vaccine series and with heterogenous SARS-CoV-2 vaccination and infection histories to 3 previously dominant variants (Ancestral, Delta, BA.5) and 3 circulating variants (XBB.1.5, EG.5, and BA.2.86) in late 2023. Analyses were performed based upon timing (within or beyond 12 months) and type (vaccine or infection) of the most recent exposure. RESULTS: Significant reduction was observed in binding antibodies, neutralization antibodies, memory B cells, and CD8+ T cells against circulating variants compared to previous variants. The reduction in antibody response was more pronounced in those whose most recent exposure was greater than 12 months from enrollment. In contrast, the CD4+ T cell response was largely consistent across all tested variants. The type of most recent exposure was not a significant factor in determining the magnitude of current immune responses. CONCLUSIONS: Administration of the XBB.1.5-based booster is likely to enhance cross-reactive humoral responses against SARS-CoV-2 circulating lineages. Ongoing surveillance of immune responses to emerging variants is needed for informing vaccine composition and timing.

Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation.

The effort to modulate challenging protein targets has stimulated interest in ligands that are larger and more complex than typical small-molecule drugs. While combinatorial techniques such as mRNA display routinely produce high-affinity macrocyclic peptides against classically undruggable targets, poor membrane permeability has limited their use toward primarily extracellular targets. Understanding the passive membrane permeability of macrocyclic peptides would, in principle, improve our ability to design libraries whose leads can be more readily optimized against intracellular targets. Here, we investigate the permeabilities of over 200 macrocyclic 10-mers using the thioether cyclization motif commonly found in mRNA display macrocycle libraries. We identified the optimal lipophilicity range for achieving permeability in thioether-cyclized 10-mer cyclic peptide-peptoid hybrid scaffolds and showed that permeability could be maintained upon extensive permutation in the backbone. In one case, changing a single amino acid from d-Pro to d-NMe-Ala, representing the loss of a single methylene group in the side chain, resulted in a highly permeable scaffold in which the low-dielectric conformation shifted from the canonical cross-beta geometry of the parent compounds into a novel saddle-shaped fold in which all four backbone NH groups were sequestered from the solvent. This work provides an example by which pre-existing physicochemical knowledge of a scaffold can benefit the design of macrocyclic peptide mRNA display libraries, pointing toward an approach for biasing libraries toward permeability by design. Moreover, the compounds described herein are a further demonstration that geometrically diverse, highly permeable scaffolds exist well beyond conventional drug-like chemical space.

Histone deacetylase expression following cisplatin-induced acute kidney injury in male and female mice.

The chemotherapeutic agent, cisplatin, accumulates in the kidneys leading to acute kidney injury (AKI). Pre-clinical and clinical studies have demonstrated sex-dependent outcomes of cisplatin-AKI. Deranged histone deacetylase (HDAC) activity is hypothesized to promote the pathogenesis of male murine cisplatin-AKI; however, it is unknown if there are sex differences in the kidney HDACs. We hypothesized that there would be sex specific Hdac expression, localization, or enzymatic activity and this may explain sexual-dimorphic responses to cisplatin-AKI. In normal human kidney RNA samples, HDAC10 was significantly greater in the kidney of women compared to men, while HDAC1, HDAC6, HDAC10, and HDAC11 were differentially expressed between the kidney cortex and medulla, regardless of sex. In a murine model of cisplatin-AKI (3 days post a 15 mg/kg injection) we found few sex- or cisplatin- Hdac kidney transcript differences among the mice. Although Hdac9 was significantly greater in female mice compared to males, HDAC9 protein localization did not differ. Hdac7 transcripts were greater in the inner medulla of cisplatin-AKI mice, regardless of sex, and this agreed with a greater HDAC7 abundance. HDAC activity within the cortex, outer, and inner medullae was significantly lower in cisplatin-AKI mice but did not differ between the sexes. In agreement with these findings a class I HDAC inhibitor didn't improve kidney injury or function. In conclusion, even though cisplatin-AKI was evident and there were transcript level differences among the different kidney regions in this model, there were few sex or cisplatin-dependent effects on kidney HDAC localization or activity.

Brain structure ages-A new biomarker for multi-disease classification.

Age is an important variable to describe the expected brain's anatomy status across the normal aging trajectory. The deviation from that normative aging trajectory may provide some insights into neurological diseases. In neuroimaging, predicted brain age is widely used to analyze different diseases. However, using only the brain age gap information (i.e., the difference between the chronological age and the estimated age) can be not enough informative for disease classification problems. In this paper, we propose to extend the notion of global brain age by estimating brain structure ages using structural magnetic resonance imaging. To this end, an ensemble of deep learning models is first used to estimate a 3D aging map (i.e., voxel-wise age estimation). Then, a 3D segmentation mask is used to obtain the final brain structure ages. This biomarker can be used in several situations. First, it enables to accurately estimate the brain age for the purpose of anomaly detection at the population level. In this situation, our approach outperforms several state-of-the-art methods. Second, brain structure ages can be used to compute the deviation from the normal aging process of each brain structure. This feature can be used in a multi-disease classification task for an accurate differential diagnosis at the subject level. Finally, the brain structure age deviations of individuals can be visualized, providing some insights about brain abnormality and helping clinicians in real medical contexts.

Estimating amino acid substitution models from genome datasets: a simulation study on the performance of estimated models.

Estimating parameters of amino acid substitution models is a crucial task in bioinformatics. The maximum likelihood (ML) approach has been proposed to estimate amino acid substitution models from large datasets. The quality of newly estimated models is normally assessed by comparing with the existing models in building ML trees. Two important questions remained are the correlation of the estimated models with the true models and the required size of the training datasets to estimate reliable models. In this article, we performed a simulation study to answer these two questions based on simulated data. We simulated genome datasets with different numbers of genes/alignments based on predefined models (called true models) and predefined trees (called true trees). The simulated datasets were used to estimate amino acid substitution model using the ML estimation methods. Our experiments showed that models estimated by the ML methods from simulated datasets with more than 100 genes have high correlations with the true models. The estimated models performed well in building ML trees in comparison with the true models. The results suggest that amino acid substitution models estimated by the ML methods from large genome datasets are a reliable tool for analyzing amino acid sequences.

Bioactivity responses to changes in mucus-associated bacterial composition between healthy and bleached Porites lobata corals.

This study aims to investigate how bioactivities of the coral surface mucus layer (SML) respond to changes in mucus-associated bacterial communities between bleached and healthy Porites lobata corals in Nha Trang Bay, Vietnam. The findings suggested that significant shifts in the mucus-associated bacterial communities were related to changes in coral health states from bleached to healthy P. lobata colonies (p < 0.05), while bacterial compositions were not significantly different across seasons and locations (p > 0.05). Of which 8 genera, Shewanella, Fusibacter, Halodesulfovibrio, Marinifilum, Endozoicomonas, Litoribacillus, Algicola, and Vibrio were present only in the SML of bleached coral while absent in the SML of the healthy one. As compared with the bleached SML, the healthy SML demonstrated stronger antibacterial activity against a coral bleaching pathogen, V. coralliilyticus, higher antitumor activity against HCT116 cell accompanied with increased induction of cleaved PARP and accelerated cell nucleic apoptosis and cycle arrest at S and G2/M phases exhibiting several typical characteristics, cell shrinkage, lost cell contact, and apoptotic body formation. Moreover, putative compounds detected at 280 nm in the healthy SML were obviously higher than those in the bleached one, probably they could be bioactive molecules responsible for competitively exclusion of pathogens, Algicola and Vibrio, from the healthy SML.

Uterocervical angle and cervical length measurements for spontaneous preterm birth prediction in low-risk singleton pregnant women: a prospective cohort study.

PURPOSE: Preterm birth is the leading cause of early neonatal morbidity and mortality. Strategies to predict preterm birth risk can help improve pregnancy outcomes. Even pregnant women without known risk factors for preterm birth can also experience it. This study aimed to evaluate the ability of the uterocervical angle and cervical length to predict spontaneous preterm birth in low-risk singleton pregnant women. METHODS: A prospective study on 1107 singleton pregnant women between 16+0 and 23+6 weeks gestation at low risk for spontaneous preterm birth who were treated at the Haiphong Hospital of Obstetrics and Gynecology, Vietnam, between September 2020 and September 2021 was conducted. A single sonographer assessed the cervical length and the uterocervical angle using transvaginal ultrasonography. The patients were followed up until delivery to determine the main pregnancy outcome (spontaneous preterm birth before 37 weeks gestation). The cut-off points for the uterocervical angle and cervical length were established by analyzing the receiver operating characteristic curve. The sensitivity, specificity, likelihood ratio, positive and negative predictive values, and accuracy of the uterocervical angle and cervical length for predicting spontaneous preterm birth were determined. RESULTS: A uterocervical angle ≥ 99° predicted spontaneous preterm birth at < 37 weeks, with a sensitivity and specificity of 91% and 76%, respectively. A cervical length ≤ 33.8 mm predicted preterm birth at < 37 weeks with a sensitivity and specificity of 25% and 66%, respectively. A uterocervical angle ≥ 99° combined with a cervical length ≤ 33.8 mm yielded the sensitivity, specificity, positive predictive value, likelihood ratio, and accuracy of spontaneous preterm birth prediction of 66%, 93%, 36%, 9, and 91%, respectively; thus provided a significant increase of specificity with an acceptable reduction of sensitivity as compared to cervical length alone. CONCLUSION: Besides the cervical length, the uterocervical angle can be considered a valuable ultrasound parameter for predicting spontaneous preterm birth in low-risk singleton pregnant women. Combining the uterocervical angle and cervical length yielded stronger spontaneous preterm birth prediction values.

Two New Benzoquinone Derivatives from Vietnamese Knema globularia Stems.

The chemical investigation of the stems of Knema globularia led to the isolation of two new benzoquinones derivatives, embenones A and B (1 and 2), along with three known compounds (3-5). The structures of the isolated compounds were determined using spectroscopic techniques, including HRESIMS, 1D and 2D NMR, in conjunction with comparison to existing literature data. Compounds 1 and 2 represent new carbon skeletons in nature. Furthermore, all isolated compounds were evaluated for their α-glucosidase inhibitory activity, with compounds 1-3 exhibiting superior potency relative to the positive control (acarbose, IC50 331 µM). Their IC50 values ranged from 1.40 to 96.1 µM.

Chemical Compositions and Antimicrobial and Mosquito Larvicidal Activities of the Leaf Essential Oils of Goniothalamus yunnanensis W.T.Wang and G. touranensis Ast: Experimental and In Silico Approaches.

The current research describes a phytochemical analysis and antimicrobial activity of essential oils extracted from the leaves of two Vietnamese Annonaceae species Goniothalamus yunnanensis W.T.Wang and G. touranensis Ast. By the GC-FID/MS (gas chromatography-flame ionization detection/mass spectrometry) analyses, sesquiterpene hydrocarbons accounted for the highest percentage of 68.22% in G. yunnanensis leaf essential oil with bicyclogermacrene (31.03%) and (E)-caryophyllene (21.12%) being the main compounds. G. touranensis leaf essential oil was dominated by monoterpene hydrocarbons (57.08%) with p-cymene (19.95%) and α-pinene (16.82%) being the major compounds. Two oil samples showed strong antibacterial effects on the Gram-positive bacteria Enterococcus faecalis ATCC51299, Staphylococcus aureus ATCC29213, and Bacillus cereus ATCC11778 with the MIC values of 16-64 µg/mL. They also inhibited the growth of the yeast Candida albicans ATCC 60193 with the same MIC value of 128 µg/mL. Both two oil samples showed strong mosquito larvicidal activity against four-instar larvae of Aedes aegypti and Ae. albopictus with the 24-h LC50 values of 16.75-27.60 µg/mL and 24-h LC90 values of 24.31-46.18 µg/mL. Docking results indicated that bicyclogermacrene and p-cymene exhibited the highest ΔG (binding affinity) values of -8.208 and -6.799 kcal/mol with the olfactory binding proteins (OBPs) of Ae. aegypti and Ae. albopictus, respectively.

Three Undescribed Furanoditerpenoids from the Tinospora crispa that Inhibit NO Production.

Phytochemical study on the methanol extract of the stems of Tinospora crispa (L.) Hook.f. & Thomson led to the isolation of thirteen compounds including three undescribed cis-clerodane-type furanoditerpenoids (1-3) and ten known ones (4-13). Their chemical structures were determined by IR, HR-ESI-MS, 1D-, and 2D-NMR spectra. Compounds 2-6 and 8 inhibited moderately NO production in LPS activated RAW 264.7 cell with the IC50 values of 83.5, 57.6, 75.3, 78.1, and 74.7 µM, respectively.

Undescribed Triterpenes from the Leaves of Syzygium myrsinifolium with Their α-Glucosidase and α-Amylase Inhibition Activity.

Two undescribed triterpenes, syzyfolium A (1) and syzyfolium B (2), together with twelve known compounds, terminolic acid (3), actinidic acid (4), piscidinol A (5), threo-dihydroxydehydrodiconiferyl alcohol (6), lariciresinol-4-O-ß-D-glucoside (7), icariol A2 (8), 14ß,15ß-dihydroxyklaineanone (9), garcimangosone D (10), (+)-catechin (11), myricetin-3-O-α-L-rhamnopyranoside (12), quercitrin (13), and 3, 4, 5-trimethoxyphenyl-(6'-O-galloyl)-O-ß-D-glucopyranoside (14) were isolated from the leaves of Syzygium myrsinifolium. Their chemical structures were determined by IR, HR-ESI-MS, 1D and 2D NMR spectra. Compounds 3 and 4 inhibited significantly α-glucosidase with IC50 values of 23.99 and 36.84, respectively, and compounds 1 and 2 inhibited significantly α-amylase with IC50 values of 35.48 and 43.65 µM, respectively.

Four New Steroidal Saponins from the Roots of Dracaena cambodiana with NO Production Inhibition Activity in LPS Activated RAW 264.7 Cells.

Seven steroidal saponins including three new 16,23-cyclocholestanes (1-3) and one new pregane (4) were isolated from the roots of Dracaena cambodiana Pierre ex Gagnep. Their chemical structures were elucidated to be (23R,25R)-26-O-ß-D-glucopyranosyl-16,23-cyclocholesta-5,17(20)-dien-22-one-3ß,16α,26-triol-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-ß-D-glucopyranoside (1), (23R,25R)-26-O-ß-D-glucopyranosyl-16,23-cyclocholesta-5,17,20(22)-trien-3ß,22,26-triol-3-O-α-L-rhamnopyranosyl-(1→3)-ß-D-glucopyranoside (2), (23R,25R)-16,23-cyclocholesta-5,16,20(22)-trien-3ß,22,26-triol-3-O-α-L-rhamnopyranosyl-(1→3)-ß-D-glucopyranoside (3), 3ß-[(O-α-L-rhamnopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-ß-D-gluco-pyranosyl)oxy]-pregna-5,17(20)-diene-16-one-20-carboxylic acid 4''''-O-ß-D-glucopyranosylisopentyl ester (4), cambodianoside A (5), diosbulbiside C (6), and diosbulbiside D (7), by IR, HR-ESI-MS, 1D and 2D NMR spectra. Compounds 1 and 4-7 inhibited nitric oxide (NO) production in lipopolysaccharide activated RAW 264.7 cells with IC50 values ranging from 19.03±1.84 to 67.92±3.81 µM, whereas compounds 2 and 3 were inactive with IC50 values over 100 µM.

Essential oil and waste hydrosol of Ocimum tenuiflorum L.: A low-cost raw material source of eugenol, botanical pesticides, and therapeutic potentiality.

In this study, essential oils and waste hydrosols of leaves of Ocimum tenuiflorum in four different geographical locations were extracted by hydrodistillation method and using gas chromatography / mass spectrometry (GC/MS) for chemical composition analysis. All four essential oil samples contained the main components (E)-ß-caryophyllene (27.8-49.0%), trans-ß-elemene (20.3-37.1%) and eugenol (9.0-44.0%). Three of the four hydrosol samples had eugenol in absolute content (94.5-98.6%), while the remaining hydrosol sample had two main components, elemicin (77.8%) and eugenol (14.2%). Essential oils and hydrosols demonstrated larvicidal activities against four important disease-transmitting mosquito species including Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, and Culex fuscocephala with 24-h LC50 values in the range 15.42-56.01 µg/mL and 53.88-97.80 µg/mL for the essential oils and the hydrosols, respectively. Essential oils and hydrosols strongly inhibited the acetylcholinesterase (AChE) enzyme of electric eels with IC50 values in the range of 25.35-107.19 µg/mL. Microemulsion (ME) can be considered as a sustainable pesticide formulation over 300 days and has improved larvicidal activity compared to free essential oil. The O. tenuiflorum in Vietnam can be considered a low-cost source of eugenol, botanical pesticides that control disease-transmitting mosquitoes, as well as having therapeutic potential to be further investigated.

Design and Implementation of a Hybrid Optical Camera Communication System for Indoor Applications.

Optical wireless communication is a promising emerging technology that addresses the limitations of radio-frequency-based wireless technologies. This study presents a new hybrid modulation method for optical camera communication (OCC), which integrates two waveforms transmitted from a single transmitter light-emitting diode (LED) and receives data through two rolling shutter camera devices on the receiver side. Then, a smart camera with a high-resolution image sensor captures the high-frequency signal, and a low-resolution image sensor from a smartphone camera captures the low-frequency signal. Based on this hybrid scheme, two data streams are transmitted from a single LED, which reduces the cost of the indoor OCC device compared with transmitting two signals from two different LEDs. In the proposed scheme, rolling-shutter orthogonal frequency-division multiplexing is used for the high-frequency signals, and M-ary frequency-shift keying is used for the low-frequency signals in the time domain. This proposed scheme is compatible with smartphone and USB cameras. By controlling the OCC parameters, the hybrid scheme can be implemented with high performance for a communication distance of 10 m.

Proximity-Based Optical Camera Communication with Multiple Transmitters Using Deep Learning.

In recent years, optical camera communication (OCC) has garnered attention as a research focus. OCC uses optical light to transmit data by scattering the light in various directions. Although this can be advantageous with multiple transmitter scenarios, there are situations in which only a single transmitter is permitted to communicate. Therefore, this method is proposed to fulfill the latter requirement using 2D object size to calculate the proximity of the objects through an AI object detection model. This approach enables prioritization among transmitters based on the transmitter proximity to the receiver for communication, facilitating alternating communication with multiple transmitters. The image processing employed when receiving the signals from transmitters enables communication to be performed without the need to modify the camera parameters. During the implementation, the distance between the transmitter and receiver varied between 1.0 and 5.0 m, and the system demonstrated a maximum data rate of 3.945 kbps with a minimum BER of 4.2×10-3. Additionally, the system achieved high accuracy from the refined YOLOv8 detection algorithm, reaching 0.98 mAP at a 0.50 IoU.

Mental health nurses' empathy towards consumers with dual diagnosis: A descriptive study.

AIM: This study aimed to assess mental health nurses' empathy towards consumers with dual diagnosis in Australian mental health settings. The research question was What is mental health nurses' empathy towards consumers with co-existing mental health and drug and alcohol problems? DESIGN AND METHODS: A cross-sectional survey was carried out to understand mental health nurses' empathy. The convenience sample included 96 mental health nurses from various mental health settings with experience working with consumers with dual diagnosis. We assessed empathy using the Toronto Empathy Questionnaire. We utilised SPSS™ software to analyse both the descriptive data and multiple-regression. RESULTS: The mean empathy score was 47.71 (SD 8.28). The analysis of the association between demographic variables and individual subscales showed an association between the clinical setting and empathy (p = .031) and sympathetic physiological arousal (p = .049). The work sector was associated with sympathetic physiological arousal (p = .045) and conspecific altruism (p = .008). Emotional contagion (ß = .98, p < .001), emotional comprehension (ß = 1.02, p < .001), sympathetic physiological arousal (ß = 1.01, p < .001) and conspecific altruism (ß = 10.23, p < .001) predicted mental health nurses' empathy. CONCLUSIONS: This study found that most mental health nurses showed empathy towards consumers with dual diagnosis. Mental health nurses who are more empathetic towards their consumers experience emotional contagion. They understand emotions better, show sympathetic physiological responses and exhibit kind behaviour towards consumers. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Further research is required to understand how mental health nurses adapt to consumers' emotional states in different mental health settings. This information can help clinicians make better decisions about care quality for consumers with dual diagnosis. IMPACT: This study addressed mental health nurses' empathy towards consumers with dual diagnosis. Mental health nurses showed increased empathy towards consumers with dual diagnosis. The empathy levels vary based on age, clinical setting, work sector and work experience. Mental health nurses' empathy levels were predicted by emotional contagion, emotion comprehension, sympathetic physiological arousal and conspecific altruism. Empathy enhancement among mental health nurses, particularly towards consumers with dual diagnosis, is crucial and should be regarded as a top priority by healthcare leaders and educators. REPORTING METHOD: Outlined by the Consensus-Based Checklist for Reporting of Survey Studies (CROSS). PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Time-course cross-species transcriptomics reveals conserved hepatotoxicity pathways induced by repeated administration of cyclosporine A.

Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate its underlying hepatotoxicity mechanism. This study aimed to capture the alterations in genome-wide expression over time and the subsequent perturbations of corresponding pathways across species. Six data from humans, mice, and rats, including animal liver tissue, human liver microtissues, and two liver cell lines exposed to CsA toxic dose, were used. The microtissue exposed to CsA for 10 d was analyzed to obtain dynamically differentially expressed genes (DEGs). Single-time points data at 1, 3, 5, 7, and 28 d of different species were used to provide additional evidence. Using liver microtissue-based longitudinal design, DEGs that were consistently up- or down-regulated over time were captured, and the well-known mechanism involved in CsA toxicity was elucidated. Thirty DEGs that consistently changed in longitudinal data were also altered in 28-d rat in-house data with concordant expression. Some genes (e.g. TUBB2A, PLIN2, APOB) showed good concordance with identified DEGs in 1-d and 7-d mouse data. Pathway analysis revealed up-regulations of protein processing, asparagine N-linked glycosylation, and cargo concentration in the endoplasmic reticulum. Furthermore, the down-regulations of pathways related to biological oxidations and metabolite and lipid metabolism were elucidated. These pathways were also enriched in single-time-point data and conserved across species, implying their biological significance and generalizability. Overall, the human organoids-based longitudinal design coupled with cross-species validation provides temporal molecular change tracking, aiding mechanistic elucidation and biologically relevant biomarker discovery.