Excited-State Dynamics of a CRABPII-Based Microbial Rhodopsin Mimic.

Microbial rhodopsin, a pivotal photoreceptor protein, has garnered widespread application in diverse fields such as optogenetics, biotechnology, biodevices, etc. However, current microbial rhodopsins are all transmembrane proteins, which both complicates the investigation on the photoreaction mechanism and limits their further applications. Therefore, a specific mimic for microbial rhodopsin can not only provide a better model for understanding the mechanism but also can extend the applications. The human protein CRABPII turns out to be a good template for design mimics on rhodopsin due to the convenience in synthesis and the stability after mutations. Recently, Geiger et al. designed a new CRABPII-based mimic M1-L121E on microbial rhodopsin with the 13-cis, syn (13C) isomerization after irradiation. However, it still remains a question as to how similar it is compared with the natural microbial rhodopsin, in particular, in the aspect of the photoreaction dynamics. In this article, we investigate the excited-state dynamics of this mimic by measuring its transient absorption spectra. Our results reveal that there are two components in the solution of mimic M1-L121E at pH 8, known as protonated Schiff base (PSB) and unprotonated Schiff base (USB) states. In both states, the photoreaction process from 13-cis, syn(13C) to all-trans,anti (AT) is faster than that from the inverse direction. In addition, the photoreaction process in the PSB state is faster than that in the USB state. We compared the isomerization time of the PSB state to that of microbial rhodopsin. Our findings indicate that M1-L121E exhibits behaviors similar to those of microbial rhodopsins in the general pattern of PSB isomerization, where the isomerization from 13C to AT is much faster than its inverse direction. However, our results also reveal significant differences in the excited-state dynamics of the mimic relative to the native microbial rhodopsin, including the slower PSB isomerization rates as well as the unusual USB photoreaction dynamics at pH = 8. By elucidating the distinctive characteristics of mimics M1-L121E, this study enhances our understanding of microbial rhodopsin mimics and their potential applications.

Human parainfluenza virus 3 vaccine candidates attenuated by codon-pair deoptimization are immunogenic and protective in hamsters.

Human parainfluenza virus type 3 (HPIV3) is a major pediatric respiratory pathogen lacking available vaccines or antiviral drugs. We generated live-attenuated HPIV3 vaccine candidates by codon-pair deoptimization (CPD). HPIV3 open reading frames (ORFs) encoding the nucleoprotein (N), phosphoprotein (P), matrix (M), fusion (F), hemagglutinin-neuraminidase (HN), and polymerase (L) were modified singly or in combination to generate 12 viruses designated Min-N, Min-P, Min-M, Min-FHN, Min-L, Min-NP, Min-NPM, Min-NPL, Min-PM, Min-PFHN, Min-MFHN, and Min-PMFHN. CPD of N or L severely reduced growth in vitro and was not further evaluated. CPD of P or M was associated with increased and decreased interferon (IFN) response in vitro, respectively, but had little effect on virus replication. In Vero cells, CPD of F and HN delayed virus replication, but final titers were comparable to wild-type (wt) HPIV3. In human lung epithelial A549 cells, CPD F and HN induced a stronger IFN response, viral titers were reduced 100-fold, and the expression of F and HN proteins was significantly reduced without affecting N or P or the relative packaging of proteins into virions. Following intranasal infection in hamsters, replication in the nasal turbinates and lungs tended to be the most reduced for viruses bearing CPD F and HN, with maximum reductions of approximately 10-fold. Despite decreased in vivo replication (and lower expression of CPD F and HN in vitro), all viruses induced titers of serum HPIV3-neutralizing antibodies similar to wt and provided complete protection against HPIV3 challenge. In summary, CPD of HPIV3 yielded promising vaccine candidates suitable for further development.

Ceramic Meta-Aerogel with Thermal Superinsulation up to 1700 °C Constructed by Self-Crosslinked Nanofibrous Network via Reaction Electrospinning.

Thermal insulation under extreme conditions requires the materials to be capable of withstanding complex thermo-mechanical stress, significant gradient temperature transition, and high-frequency thermal shock. The excellent structural and functional properties of ceramic aerogels make them attractive for thermal insulation. However, in extremely high-temperature environments (above 1500 °C), they typically exhibit limited insulation capacity and thermo-mechanical stability, which may lead to catastrophic accidents, and this problem is never effectively addressed. Here, a novel ceramic meta-aerogel constructed from a crosslinked nanofiber network using a reaction electrospinning strategy, which ensures excellent thermo-mechanical stability and superinsulation under extreme conditions, is designed. The ceramic meta-aerogel has an ultralow thermal conductivity of 0.027 W m-1 k-1, and the cold surface temperature is only 303 °C in a 1700 °C high-temperature environment. After undergoing a significant gradient temperature transition from liquid nitrogen to 1700 °C flame burning, the ceramic meta-aerogel can still withstand thousands of shears, flexures, compressions, and other complex forms of mechanical action without structural collapse. This work provides a new insight for developing ceramic aerogels that can be used for a long period in extremely high-temperature environments.

Construction and Validation of a Prognostic Model Based on Mitochondrial Genes in Prostate Cancer.

This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.

NAD activates olfactory receptor 1386 to regulate type I interferon responses in Plasmodium yoelii YM infection.

Olfactory receptors (Olfr) are G protein-coupled receptors that are normally expressed on olfactory sensory neurons to detect volatile chemicals or odorants. Interestingly, many Olfrs are also expressed in diverse tissues and function in cell-cell recognition, migration, and proliferation as well as immune responses and disease processes. Here, we showed that many Olfr genes were expressed in the mouse spleen, linked to Plasmodium yoelii genetic loci significantly, and/or had genome-wide patterns of LOD scores (GPLSs) similar to those of host Toll-like receptor genes. Expression of specific Olfr genes such as Olfr1386 in HEK293T cells significantly increased luciferase signals driven by IFN-ß and NF-κB promoters, with elevated levels of phosphorylated TBK1, IRF3, P38, and JNK. Mice without Olfr1386 were generated using the CRISPR/Cas9 method, and the Olfr1386-/- mice showed significantly lower IFN-α/ß levels and longer survival than wild-type (WT) littermates after infection with P. yoelii YM parasites. Inhibition of G protein signaling and P38 activity could affect cyclic AMP-responsive element promoter-driven luciferase signals and IFN-ß mRNA levels in HEK293T cells expressing the Olfr1386 gene, respectively. Screening of malaria parasite metabolites identified nicotinamide adenine dinucleotide (NAD) as a potential ligand for Olfr1386, and NAD could stimulate IFN-ß responses and phosphorylation of TBK1 and STAT1/2 in RAW264.7 cells. Additionally, parasite RNA (pRNA) could significantly increase Olfr1386 mRNA levels. This study links multiple Olfrs to host immune response pathways, identifies a candidate ligand for Olfr1386, and demonstrates the important roles of Olfr1386 in regulating type I interferon (IFN-I) responses during malaria parasite infections.

A novel NTRK1 splice site variant causing congenital insensitivity to pain with anhidrosis in a Chinese family.

Background: Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy type Ⅳ (HSAN-IV), is a rare autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, insensitivity to noxious stimuli, self-mutilating behavior and intellectual disability. CIPA can be caused by the variants in NTRK1 gene, which encodes a high-affinity tyrosine kinase receptor for nerve growth factor. To ascertain the hereditary cause of a patient with CIPA accompanied by the additional symptoms of mild growth retardation, prone to fracture, underdeveloped nails of fingers and toes, irregular tooth alignment, enamel hypoplasia, postoperative wound healing difficulty, hand and limb deformity, and dislocation of hip joint, whole exome sequencing was used and revealed a compound heterozygous variant in NTRK1. Methods: DNA was extracted from peripheral blood samples of pediatric patients and their parents, and subjected to comprehensive analysis using whole-exome sequencing (WES), followed by verification of variant sites in the NTRK1 gene through Sanger sequencing. To elucidate the functional impact of the newly discovered variants, an in vitro experimental system was established. Splicing analysis was conducted using PCR and Sanger sequencing, while expression levels were assessed through qPCR and Western blot techniques. Results: One hotspot variant c.851-33T>A(ClinVar ID: 21308) and a novel variant c.850 + 5G>A(ClinVar ID:3069176) was inherited from her father and mother, respectively, identified in the affected individuals. The c.850 + 5G>A variant in NTRK1 resulted in two forms of aberrant mRNA splicing: 13bp deletion (c.838_850del13, p. Val280Ser fs180) and 25bp deletion (826_850del25, p. Val276Ser fs180) in exon 7, both leading to a translational termination at a premature stop codon and forming a C-terminal truncated protein. The expression of two abnormal splicing isoforms was decreased both in the level of mRNA and protein. Conclusion: In conclusion, this study elucidated the genetic cause of a patient with CIPA and identified a novel variant c.850 + 5G>A in NTRK1, which broadened the and enriched the NTRK1 mutation spectrum.

The effect of illness perception on psychosocial adjustment of patients with breast cancer and their spouses: actor-partner independence model.

OBJECTIVE: With the increase in the prevalence rate and improvements in the survival of breast cancer patients, there is a growing interest in understanding the level of psychosocial adjustment in these patients. The study aimed to describe the illness perception and psychosocial adjustment levels of both breast cancer patients and their spouses, to use the Actor-Partner Interdependence Model (APIM) to clarify the actor-partner relationships between spouses, and to explore the impact of illness perception on psychosocial adjustment to the disease within the joint actions of both spouses. METHODS: A total of 216 female patients with breast cancer and their spouses participated in the study. They were selected from two tertiary hospitals in Guangdong Province, China from October 2022 to May 2023 using a convenience sampling method. The participants were assessed using the Brief Illness Perception Questionnaire and the Psychosocial Adjustment to Illness Scale to examine the relationship between illness perception and psychosocial adjustment. AMOS24.0 was used to test and analyze the actor-partner interdependence model. RESULTS: The illness perception score (57.75 ± 10.91) was slightly higher than that of the spouse (57.10 ± 11.00), and the psychosocial adjustment score (64.67 ± 6.33) was slightly lower than that of the spouse (64.76 ± 7.49). The results of the actor-partner interdependence model indicated that there was a couple partner between breast cancer patients and their spouses: the spouse's illness perception significantly affected the patient's psychosocial adjustment (ß = 0.095, p = 0.015); the patient's illness perception also significantly affected the spouse's psychosocial adjustment (ß = 0.106, p = 0.033). Among them, the patient's psychosocial adjustment was found to be related to the patient's illness comprehensibility or coherence of illness (ß = 0.433, p = 0.009), the spouse's emotional illness representation (ß = 0.218, p = 0.037), and the spouse's illness comprehensibility or coherence of illness (ß = 0.416, p = 0.007), while the spouse's psychosocial adjustment was only related to the spouse's illness comprehensibility or coherence of illness (ß = 0.528, p = 0.007). CONCLUSIONS: The psychosocial adjustment of breast cancer patients is affected by both their own and spouse's illness perception. Therefore, in the future, the healthcare staff can implement early psychological interventions for patients diagnosed with breast cancer and their spouses as a unit to promote the psychosocial adjustment of them.

A whole-exome sequencing study of patent foramen ovale: investigating genetic variants and their association with cardiovascular disorders.

Background: Patent foramen ovale (PFO) has a genetic predisposition and is closely associated with cryptogenic stroke (CS), migraine, decompression sickness, and hypoxemia. Identifying PFO-related mutant genes through whole-exome sequencing (WES) can help in the early recognition of cardiovascular genetic risk factors, guide timely clinical intervention, and reduce the occurrence of cardiovascular events. Methods: We analyzed mutant genes from ClinVar and OMIM databases. WES was performed on 25 PFO patients from Zhejiang Provincial Hospital of Chinese Medicine. Pathogenicity of variants was evaluated using American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology. (AMP) guidelines. Results: In ClinVar (4 Feb 2023), 113 coding gene mutations were found, including 83 associated with PFO. From OMIM (18 Apr 2023), 184 gene mutations were analyzed, with 110 mutant coding genes. WES identified pathogenic mutations in two of 25 PFO patients (8%). LDLR, SDHC, and NKX2-5 genes were linked to PFO and primarily involved in myocardial tissue function. NKX2-5 may play a crucial role in PFO development, interacting with NOTCH1, GATA4, MYH6, SCN5A signaling pathways regulating cardiomyocyte characteristics. Conclusion: We identified pathogenic mutations in LDLR, SDHC, and NKX2-5 genes, implying their role in PFO development. Functional enrichment analysis revealed NKX2-5's interaction with signaling pathways regulating cardiomyocyte function. These findings enhance our understanding of PFO's genetic basis, suggesting potential therapeutic targets for future research.

Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo.

Exploring novel diagnostic and therapeutic biomarkers is extremely important for osteosarcoma. YME1 Like 1 ATPase (YME1L), locating in the mitochondrial inner membrane, is key in regulating mitochondrial plasticity and metabolic activity. Its expression and potential functions in osteosarcoma are studied in the present study. We show that YME1L mRNA and protein expression is significantly elevated in osteosarcoma tissues derived from different human patients. Moreover, its expression is upregulated in various primary and immortalized osteosarcoma cells. The Cancer Genome Atlas database results revealed that YME1L overexpression was correlated with poor overall survival and poor disease-specific survival in sarcoma patients. In primary and immortalized osteosarcoma cells, silencing of YME1L through lentiviral shRNA robustly inhibited cell viability, proliferation, and migration. Moreover, cell cycle arrest and apoptosis were detected in YME1L-silenced osteosarcoma cells. YME1L silencing impaired mitochondrial functions in osteosarcoma cells, causing mitochondrial depolarization, oxidative injury, lipid peroxidation and DNA damage as well as mitochondrial respiratory chain complex I activity inhibition and ATP depletion. Contrarily, forced YME1L overexpression exerted pro-cancerous activity and strengthened primary osteosarcoma cell proliferation and migration. YME1L is important for Akt-S6K activation in osteosarcoma cells. Phosphorylation of Akt and S6K was inhibited after YME1L silencing in primary osteosarcoma cells, but was strengthened with YME1L overexpression. Restoring Akt-mTOR activation by S473D constitutively active Akt1 mitigated YME1L shRNA-induced anti-osteosarcoma cell activity. Lastly, intratumoral injection of YME1L shRNA adeno-associated virus inhibited subcutaneous osteosarcoma xenograft growth in nude mice. YME1L depletion, mitochondrial dysfunction, oxidative injury, Akt-S6K inactivation, and apoptosis were detected in YME1L shRNA-treated osteosarcoma xenografts. Together, overexpressed YME1L promotes osteosarcoma cell growth, possibly by maintaining mitochondrial function and Akt-mTOR activation.

Effects of bilateral tDCS over DLPFC on response inhibition, craving, and brain functional connectivity in Internet gaming disorder: A randomized, double-blind, sham-controlled trial with fMRI.

Background and aims: Impaired inhibitory control accompanied by enhanced craving is hallmark of addiction. This study investigated the effects of transcranial direct current stimulation (tDCS) on response inhibition and craving in Internet gaming disorder (IGD). We examined the brain changes after tDCS and their correlation with clinical variables. Methods: Twenty-four males with IGD were allocated randomly to an active or sham tDCS group, and data from 22 participants were included for analysis. Participants self-administered bilateral tDCS over the dorsolateral prefrontal cortex (DLPFC) for 10 sessions. Stop-signal tasks were conducted to measure response inhibition and participants were asked about their cravings for Internet gaming at baseline and post-tDCS. Functional magnetic resonance imaging data were collected at pre- and post-tDCS, and group differences in resting-state functional connectivity (rsFC) changes from the bilateral DLPFC and nucleus accumbens were examined. We explored the relationship between changes in the rsFC and behavioral variables in the active tDCS group. Results: A significant group-by-time interaction was observed in response inhibition. After tDCS, only the active group showed a decrease in the stop-signal reaction time (SSRT). Although craving decreased, there were no significant group-by-time interactions or group main effects. The anterior cingulate cortex (ACC) showed group differences in post- versus pre-tDCS rsFC from the right DLPFC. The rsFC between the ACC and left middle frontal gyrus was negatively correlated with the SSRT. Discussion and conclusion: Our study provides preliminary evidence that bilateral tDCS over the DLPFC improves inhibitory control and could serve as a therapeutic approach for IGD.

Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia.

PURPOSE: The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community. EXPERIMENTAL DESIGN: We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models. RESULTS: We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia. CONCLUSIONS: Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.

The LANCET robotic system can improve surgical efficiency in total hip arthroplasty: A prospective randomized, multicenter, parallel-controlled clinical trial.

Objective: To evaluate the accuracy and safety of the LANCET robotic system, a robot arm assisted operation system for total hip arthroplasty via a multicenter clinical randomized controlled trial. Methods: A total of 116 patients were randomized into two groups: LANCET robotic arm assisted THA group (N = 58) and the conventional THA group (N = 58). General information about the patients was collected preoperatively. Operational time and bleeding were recorded during the surgery. The position of the acetabular prosthesis was evaluated by radiographs one week after surgery and compared with preoperative planning. Harris score, hip mobility, prosthesis position and angle and complications were compared between the two groups at three months postoperatively. Results: None of the 111 patients who ultimately completed the 3-month follow-up experienced adverse events such as hip dislocation and infection during follow-up. In the RAA group, 52 (92.9 %) patients were located in the Lewinnek safe zone and 49 (87.5 %) patients were located in the Callanan safe zone. In the control group were 47 (85.5 %) and 44 (80.0 %) patients, respectively. In the RAA group, 53 (94.6 %) patients had a postoperative acetabular inclination angle and 51 (91.1 %) patients had an acetabular version angle within a deviation of 5° from the preoperative plan. These numbers were significantly higher than those of the control group, which consisted of 42 (76.4 %) and 34 (61.8 %) patients respectively. There were no significant differences between the two groups of subjects in terms of general condition, intraoperative bleeding, hip mobility, and adverse complications. Conclusion: The results of this prospective randomized, multicenter, parallel-controlled clinical study demonstrated that the LANCET robotic system leads conventional THA surgery in accuracy of acetabular cup placement and does not differ from conventional THA surgery in terms of postoperative hip functional recovery and complications. The translational potential of this article: In the past, the success rate of total hip arthroplasty (THA) relied heavily on the surgeon's experience. As a result, junior doctors needed extensive training to become proficient in this technique. However, the introduction of surgical robots has significantly improved this situation. By utilizing robotic assistance, both junior and senior doctors can perform THA quickly and efficiently. This advancement is crucial for the widespread adoption of THA, as patients can now receive surgical treatment in local facilities instead of overwhelming larger hospitals and straining medical resources. Moreover, the development of surgical robots with fully independent intellectual property rights holds immense value in overcoming the limitations of high-end medical equipment. This aligns with the objectives outlined in the 14th Five Year Plan for National Science and Technology Strategy.

Utilization of plant-derived sugars and lipids are coupled during colonization of rhizoplane and rhizosphere by the fungus Metarhizium robertsii.

Plant-derived sugars and lipids are key nutritional sources for plant associated fungi. However, the relationship between utilization of host-derived sugars and lipids during development of the symbiotic association remains unknown. Here we show that the fungus Metarhizium robertsii also needs plant-derived lipids to develop symbiotic relationship with plants. The fatty acid binding proteins FABP1 and FABP2 are important for utilization of plant-derived lipids as the deletion of Fabp1 and Fabp2 significantly reduced the ability of M. robertsii to colonize rhizoplane and rhizosphere of maize and Arabidopsis thaliana. Deleting Fabp1 and Fabp2 increased sugar utilization by upregulating six sugar transporters, and this explains why deleting the monosaccharide transporter gene Mst1, which plays an important role in utilization of plant-derived sugars, had no impact on the ability of the double-gene deletion mutant ΔFabp1::ΔFabp2 to colonize plant roots. FABP1 and FABP2 were also found in other plant-associated Metarhizium species, and they were highly expressed in the medium using the tomato root exudate as the sole carbon and nitrogen source, suggesting that they could be also important for these species to develop symbiotic relationship with plants. In conclusion, we discovered that utilization of plant-derived sugars and lipids are coupled during colonization of rhizoplane and rhizosphere by M. robertsii.

Mastigoneme structure reveals insights into the O-linked glycosylation code of native hydroxyproline-rich helices.

Hydroxyproline-rich glycoproteins (HRGPs) are a ubiquitous class of protein in the extracellular matrices and cell walls of plants and algae, yet little is known of their native structures or interactions. Here, we used electron cryomicroscopy (cryo-EM) to determine the structure of the hydroxyproline-rich mastigoneme, an extracellular filament isolated from the cilia of the alga Chlamydomonas reinhardtii. The structure demonstrates that mastigonemes are formed from two HRGPs (a filament of MST1 wrapped around a single copy of MST3) that both have hyperglycosylated poly(hydroxyproline) helices. Within the helices, O-linked glycosylation of the hydroxyproline residues and O-galactosylation of interspersed serine residues create a carbohydrate casing. Analysis of the associated glycans reveals how the pattern of hydroxyproline repetition determines the type and extent of glycosylation. MST3 possesses a PKD2-like transmembrane domain that forms a heteromeric polycystin-like cation channel with PKD2 and SIP, explaining how mastigonemes are tethered to ciliary membranes.

Diagnostic accuracy of magnetically guided capsule endoscopy with a detachable string for detecting oesophagogastric varices in adults with cirrhosis: prospective multicentre study.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of using magnetically guided capsule endoscopy with a detachable string (ds-MCE) for detecting and grading oesophagogastric varices in adults with cirrhosis. DESIGN: Prospective multicentre diagnostic accuracy study. SETTING: 14 medical centres in China. PARTICIPANTS: 607 adults (>18 years) with cirrhosis recruited between 7 January 2021 and 25 August 2022. Participants underwent ds-MCE (index test), followed by oesophagogastroduodenoscopy (OGD, reference test) within 48 hours. The participants were divided into development and validation cohorts in a ratio of 2:1. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity and specificity of ds-MCE in detecting oesophagogastric varices compared with OGD. Secondary outcomes included the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices and the diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices. RESULTS: ds-MCE and OGD examinations were completed in 582 (95.9%) of the 607 participants. Using OGD as the reference standard, ds-MCE had a sensitivity of 97.5% (95% confidence interval 95.5% to 98.7%) and specificity of 97.8% (94.4% to 99.1%) for detecting oesophagogastric varices (both P<0.001 compared with a prespecified 85% threshold). When using the optimal 18% threshold for luminal circumference of the oesophagus derived from the development cohort (n=393), the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices in the validation cohort (n=189) were 95.8% (89.7% to 98.4%) and 94.7% (88.2% to 97.7%), respectively. The diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices was 96.3% (92.6% to 98.2%), 96.9% (95.2% to 98.0%), and 96.7% (95.0% to 97.9%), respectively. Two serious adverse events occurred with OGD but none with ds-MCE. CONCLUSION: The findings of this study suggest that ds-MCE is a highly accurate and safe diagnostic tool for detecting and grading oesophagogastric varices and is a promising alternative to OGD for screening and surveillance of oesophagogastric varices in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03748563.

Distribution and bulk flow analyses of the intraflagellar transport (IFT) motor kinesin-2 support an "on-demand" model for Chlamydomonas ciliary length control.

Most cells tightly control the length of their cilia. The regulation likely involves intraflagellar transport (IFT), a bidirectional motility of multi-subunit particles organized into trains that deliver building blocks into the organelle. In Chlamydomonas, the anterograde IFT motor kinesin-2 consists of the motor subunits FLA8 and FLA10 and the nonmotor subunit KAP. KAP dissociates from IFT at the ciliary tip and diffuses back to the cell body. This observation led to the diffusion-as-a-ruler model of ciliary length control, which postulates that KAP is progressively sequestered into elongating cilia because its return to the cell body will require increasingly more time, limiting motor availability at the ciliary base, train assembly, building block supply, and ciliary growth. Here, we show that Chlamydomonas FLA8 also returns to the cell body by diffusion. However, more than 95% of KAP and FLA8 are present in the cell body and, at a given time, just ~1% of the motor participates in IFT. After repeated photobleaching of both cilia, IFT of fluorescent kinesin subunits continued indicating that kinesin-2 cycles from the large cell-body pool through the cilia and back. Furthermore, growing and full-length cilia contained similar amounts of kinesin-2 subunits and the size of the motor pool at the base changed only slightly with ciliary length. These observations are incompatible with the diffusion-as-a-ruler model, but rather support an "on-demand model," in which the cargo load of the trains is regulated to assemble cilia of the desired length.

Changes in the etiology of liver cirrhosis and the corresponding management strategies.

We read with interest the article by Xing Wang, which was published in the recent issue of the World Journal of Hepatology 2023; 15: 1294-1306. This article focuses particularly on the prevalence and trends in the etiology of liver cirrhosis (LC), prognosis for patients suffering from cirrhosis-related complications and hepatocellular carcinoma (HCC), and management strategies. The etiology of cirrhosis varies according to geographical, economic, and population factors. Viral hepatitis is the dominant cause in China. Vaccination and effective treatment have reduced the number of people with viral hepatitis, but the overall number is still large. Patients with viral hepatitis who progress over time to LC and HCC remain an important population to manage. The increased incidence of metabolic syndrome and alcohol consumption is likely to lead to a potential exponential increase in metabolic dysfunction-associated steatotic liver disease (MASLD)-associated LC and alcoholic liver disease in the future. Investigating the evolution of the etiology of LC is important for guiding the direction of future research and policy development. These changing trends indicate a need for greater emphasis on tackling obesity and diabetes, and implementing more effective measures to regulate alcohol consumption in order to reduce the occurrence of MASLD. In an effort to help cope with these changing trends, the authors further proposed countermeasures for healthcare authorities doctors, and patients.

METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients.

Background: N6-methyladenosine (m6A) is the most frequently occurring interior modification in eukaryotic messenger RNA (mRNA), and abnormal mRNA modifications can affect many biological processes. However, m6A's effect on the metabolism of antiplatelet drugs for the prevention of ischemic stroke (IS) remains largely unclear. Methods: We analyzed the m6A enzymes and m6A methylation in peripheral blood samples of IS patients with/without clopidogrel resistance (CR), and the peripheral blood and liver of rat models with/without CR. We also compared the effect of m6A methylation on the expression of the drug-metabolizing enzymes (CYP2C19 and CYP2C6v1) in CR and non-CR samples. Results: Methyltransferase-like 3 (METTL3), an m6A enzyme, was highly expressed in the peripheral blood of patients with CR, and in both the peripheral blood and liver of rats with CR. This enzyme targets CYP2C19 or CYP2C6v1 mRNA through m6A methylation, resulting in low expression of CYP2C19 or CYP2C6v1 mRNA. Consequently, this leads to decreased clopidogrel metabolism and CR. Conclusion: The METTL3-mediated methylation of CYP2C19 mRNA may aggravate CR in IS patients.

Partial order relation-based gene ontology embedding improves protein function prediction.

Protein annotation has long been a challenging task in computational biology. Gene Ontology (GO) has become one of the most popular frameworks to describe protein functions and their relationships. Prediction of a protein annotation with proper GO terms demands high-quality GO term representation learning, which aims to learn a low-dimensional dense vector representation with accompanying semantic meaning for each functional label, also known as embedding. However, existing GO term embedding methods, which mainly take into account ancestral co-occurrence information, have yet to capture the full topological information in the GO-directed acyclic graph (DAG). In this study, we propose a novel GO term representation learning method, PO2Vec, to utilize the partial order relationships to improve the GO term representations. Extensive evaluations show that PO2Vec achieves better outcomes than existing embedding methods in a variety of downstream biological tasks. Based on PO2Vec, we further developed a new protein function prediction method PO2GO, which demonstrates superior performance measured in multiple metrics and annotation specificity as well as few-shot prediction capability in the benchmarks. These results suggest that the high-quality representation of GO structure is critical for diverse biological tasks including computational protein annotation.

Metabolomic Biomarkers of Dietary Approaches to Stop Hypertension (DASH) Dietary Patterns in Pregnant Women.

Objective: the aim of this study was to identify plasma metabolomic markers of Dietary Approaches to Stop Hypertension (DASH) dietary patterns in pregnant women. Methods: This study included 186 women who had both dietary intake and metabolome measured from a nested case-control study within the NICHD Fetal Growth Studies-Singletons cohort (FGS). Dietary intakes were ascertained at 8-13 gestational weeks (GW) using the Food Frequency Questionnaire (FFQ) and DASH scores were calculated based on eight food and nutrient components. Fasting plasma samples were collected at 15-26 GW and untargeted metabolomic profiling was performed. Multivariable linear regression models were used to examine the association of individual metabolites with the DASH score. Least absolute shrinkage and selection operator (LASSO) regression was used to select a panel of metabolites jointly associated with the DASH score. Results: Of the total 460 known metabolites, 92 were individually associated with DASH score in linear regressions, 25 were selected as a panel by LASSO regressions, and 18 were identified by both methods. Among the top 18 metabolites, there were 11 lipids and lipid-like molecules (i.e., TG (49:1), TG (52:2), PC (31:0), PC (35:3), PC (36:4) C, PC (36:5) B, PC (38:4) B, PC (42:6), SM (d32:0), gamma-tocopherol, and dodecanoic acid), 5 organic acids and derivatives (i.e., asparagine, beta-alanine, glycine, taurine, and hydroxycarbamate), 1 organic oxygen compound (i.e., xylitol), and 1 organoheterocyclic compound (i.e., maleimide). Conclusions: our study identified plasma metabolomic markers for DASH dietary patterns in pregnant women, with most of being lipids and lipid-like molecules.