A genomic compendium of cultivated human gut fungi characterizes the gut mycobiome and its relevance to common diseases.

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.

Novel Quantitative Contrast Sensitivity Function Enhances the Prediction of Treatment Outcome and Recurrence in Amblyopia.

Purpose: Although effective amblyopia treatments are available, treatment outcome is unpredictable, and the condition recurs in up to 25% of the patients. We aimed to evaluate whether a large-scale quantitative contrast sensitivity function (CSF) data source, coupled with machine learning (ML) algorithms, can predict amblyopia treatment response and recurrence in individuals. Methods: Visual function measures from traditional chart vision acuity (VA) and novel CSF assessments were used as the main predictive variables in the models. Information from 58 potential predictors was extracted to predict treatment response and recurrence. Six ML methods were applied to construct models. The SHapley Additive exPlanations was used to explain the predictions. Results: A total of 2559 consecutive records of 643 patients with amblyopia were eligible for modeling. Combining variables from VA and CSF assessments gave the highest accuracy for treatment response prediction, with the area under the receiver operating characteristic curve (AUC) of 0.863 and 0.815 for outcome predictions after 3 and 6 months, respectively. Variables from the VA assessment alone predicted the treatment response, with AUC values of 0.723 and 0.675 after 3 and 6 months, respectively. Variables from the CSF assessment gave rise to an AUC of 0.909 for recurrence prediction compared to 0.539 for VA assessment alone, and adding VA variables did not improve predictive performance. The interocular differences in CSF features are significant contributors to recurrence risk. Conclusions: Our models showed CSF data could enhance treatment response prediction and accurately predict amblyopia recurrence, which has the potential to guide amblyopia management by enabling patient-tailored decision making.

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Lipid profile alterations in non-infectious uveitis: correlation with quantitative optical coherence tomography angiography parameters.

BACKGROUND/AIMS: Lipid profiles have been changed in numerous chronic conditions. The impact of uveitis on lipid metabolism remains unclear. METHODS: This is a cross-sectional study included 416 patients with non-infectious uveitis (NIU) and 416 healthy subjects. Standard techniques were used to measure total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDLc), low-density lipoprotein-cholesterol (LDLc) levels. Quantitative optical coherence tomography angiography (OCTA) parameters were obtained from 500 eyes in each group. Correlation analysis examined the relationship between lipid profile and OCTA parameters. RESULTS: Patients with NIU exhibited significantly elevated TC, TG and LDLc levels compared with controls (p=0.003; p<0.001; p<0.001, respectively). Subgroup analysis revealed that HDLc was significantly lower in Behçet's disease (p=0.024) compared with controls. Vascular density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris and optic disk were significantly decreased in NIU eyes (p<0.05, respectively) compared with controls. HDLc exhibited a significant negative correlation with VDs in the whole and parafovea SCP (r=-0.489, p=0.008; r=-0.480, p=0.0026, respectively), while LDLc showed a significant positive correlation with VDs in the whole and parafovea DCP in NIU patients (r=0.576, p=0.032; r=0.267, p=0.034, respectively). CONCLUSIONS: The lipid profile is altered in NIU, and there are correlations between HDLc and LDLc levels and VD as measured by OCTA. Lipid profile analysis may offer valuable insights into evaluating vascular and metabolic aspects of NIU.

Preparation and measurement of a sandwiched Sn atomic beam source for laser resonance ionization mass spectrometry.

Isotope analysis of Sn plays a crucial role in geochemical studies and in monitoring nuclear contamination. Nevertheless, prevalent analytical techniques for examining Sn isotopes encounter the issue of isobaric interference, markedly impacting the accuracy of the test results. Laser resonance ionization mass spectrometry (LRIMS) can effectively overcome the difficulties associated with the isobaric interference inherent in commercial mass spectrometry. In this paper, different amounts of Sn were prepared on Re filaments by electrodeposition and tested via LRIMS. The results showed that the average detection efficiency of LRIMS decreased with increasing total Sn content from 1 µg to 4 µg, and the fluctuations in the test results among the samples increased significantly. Therefore, the electrodeposition process, as well as the composition and morphology of the deposits were characterized by SEM, EDS and XPS; results showed that the degradation of the samples with increasing Sn content was attributed to the complexity of the composition, micro-structure, valence of the deposits, and the interference of various elements. To cope with the anomalies encountered above, the deposits were heat-treated at 600 °C in a hydrogen atmosphere to eliminate detrimental impurities, like Cl, and Sn was effectively reduced to an almost singular atomic state. Furthermore, a titanium layer was covered on the surface of the heat-treated deposit by magnetron sputtering. Ultimately, a highly efficient and stable Sn atomic beam source with a sandwiched structure has been successfully developed and exhibits broad application prospect.

Confidential multiple-input multiple-output optical camera communication aided by a two-dimensional pilot.

Optical camera communication (OCC) has attracted increased attention for its inherent security advantage. However, there still exists the risk of eavesdropping on the broadcasting channel of OCC. To achieve confidential communication, we propose the confidentiality-interference dual light-emitting diode (LED) communication (CIDLC) scheme at the transmitter (TX) and elimination of interference (EI) scheme at the receiver (RX). Meanwhile, interference signals refer to the bit shift of confidential signals. Further, we propose the two-dimensional pilot-aided channel estimation (2D-PACE) scheme to enhance the reliability of multiple-input multiple-output (MIMO) OCC. Experiment results validate the effectiveness of our schemes, which guarantee confidentiality while performing well at a 2 m non-line-of-sight (NLOS) distance. Finally, the communication-illumination integration OCC is constructed via the energy equalization coding (EEC) scheme.

Diffusion-tensor-imaging 1-year-old and 2-year-old infant brain atlases with comprehensive gray and white matter labels.

Human infancy is marked by fastest postnatal brain structural changes. It also coincides with the onset of many neurodevelopmental disorders. Atlas-based automated structure labeling has been widely used for analyzing various neuroimaging data. However, the relatively large and nonlinear neuroanatomical differences between infant and adult brains can lead to significant offsets of the labeled structures in infant brains when adult brain atlas is used. Age-specific 1- and 2-year-old brain atlases covering all major gray and white matter (GM and WM) structures with diffusion tensor imaging (DTI) and structural MRI are critical for precision medicine for infant population yet have not been established. In this study, high-quality DTI and structural MRI data were obtained from 50 healthy children to build up three-dimensional age-specific 1- and 2-year-old brain templates and atlases. Age-specific templates include a single-subject template as well as two population-averaged templates from linear and nonlinear transformation, respectively. Each age-specific atlas consists of 124 comprehensively labeled major GM and WM structures, including 52 cerebral cortical, 10 deep GM, 40 WM, and 22 brainstem and cerebellar structures. When combined with appropriate registration methods, the established atlases can be used for highly accurate automatic labeling of any given infant brain MRI. We demonstrated that one can automatically and effectively delineate deep WM microstructural development from 3 to 38 months by using these age-specific atlases. These established 1- and 2-year-old infant brain DTI atlases can advance our understanding of typical brain development and serve as clinical anatomical references for brain disorders during infancy.

Specific Knockout of Notch-1 in Macrophages Modulate the Progression of Hepatic Insulin Resistance in HFD Fed Mice via Regulating IRE1α-XBP1 Signals.

OBJECTIVE: To develop an intervention based on Notch-1 signalling pathway blockade by investigating the potential application of the neurogenic locus notch homologue protein 1(Notch-1) signalling pathway as a key regulator of chronic inflammation and adipogenesis in the treatment of hepatic insulin resistance (HIR). STUDY DESIGN: Experimental study. Place and Duration of the Study: Animal Laboratory of the Fourth Hospital of Hebei Medical University, Shijiazhuang, China, from April 2021 to June 2022. METHODOLOGY: HIR models were established in Notch-1WT and Notch-1MAC-KO mice by high fat diet (HFD) for 16 weeks. Haematoxylin and eosin (HE) staining and oil red O (ORO) staining were used to detect inflammatory infiltration and lipid accumulation in each group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of TNF-α and IL-6. Free fatty acid (FFA) and total cholesterol (TC) were measured with relevant kits. Moreover, real-time quantitative polymerase chain reaction (PCR) was performed to detect the relative expressions of F4/80, Mcp1, and CD11b in hepatic tissues. Mass spectrometry was used to analyse the levels of triglyceride (TG), diacylglycerol (DAG) and conformite europeenne (CE) in liver tissue. Western blotting was used to detect the expression of related proteins. RESULTS: Specific knockdown of Notch-1 in macrophages decreases the relative fluorescence intensity of CD68 and attenuates inflammatory infiltration and lipid degeneration. There was no difference in plasma levels of FFA and TG. Specific knockdown of Notch-1 in macrophages decreases the expression of F4/80, Mcp1, and CD11b, as well as the levels of TG, DAG, CE, IL-6, and TNF-α. CONCLUSION: Specific knockout of Notch-1 in macrophages may reduce HIR by inhibiting the IRE1α-XBP1 signalling pathway. KEY WORDS: Hepatic insulin resistance, Macrophages, Notch-1, IRE1α, XBP1.

Validity of A Novel Simulator for Percutaneous Transforaminal Endoscopic Discectomy.

BACKGROUND: Percutaneous transforaminal endoscopic discectomy (PTED) has steep learning curves and a high incidence of complications, but currently, efficient and economical training methods are lacking. This study aimed to validate a novel simulator for PTED. METHODS: The simulated PTED included puncturing and establishing the working channel (PEWC) and endoscopic discectomy, with the PEWC being the tested module. Eleven experts and 21 novices were included and introduced to the simulator and tasks; all participants completed the PEWC. Outcomes included: total operation time, number of fluoroscopy for positioning the working sheath, number of spinal risk region invasion, Global Rating Scale (GRS) and a modified GRS, etc. The Mann-Whitney U test was used to compare 2 groups. Spearman's correlation coefficient analyzed continuous variables. RESULTS: Experts outperformed novices in total operation time (P = 0.001), requiring fewer number of fluoroscopies for positioning the working sheath (P = 0.003). Additionally, experts had a lower number of spinal risk region invasions (P = 0.016) and higher scores on both the GRS (P < 0.001) and modified GRS (P < 0.001). PTED experience correlated with GRS scores (P = 0.001) and modified GRS (P < 0.001). The overall realism scored a median of 4 (3.75-5), and educational value had a median of 4 (range 3-5). CONCLUSIONS: This study demonstrates the validity of the novel simulator, revealing significant associations between PTED experience and performance metrics in a simulated PEWC setting. Furthermore, the PEWC module also offers a good realistic design and high education value according to experts.

Synergistic effect of chitosan and ß-carotene in inhibiting MNU-induced retinitis pigmentosa.

In this study, N-Methyl-N-nitrosourea (MNU) was intraperitoneally injected to construct a mouse retinitis pigmentosa (RP) model to evaluate the protective effect of chitosan and ß-carotene on RP. The results demonstrated that chitosan synergized with ß-carotene significantly reduced retinal histopathological structural damage in RP mice. The co-treatment group of ß-carotene and chitosan restored the retinal thickness and outer nuclear layer thickness better than the group treated with the two alone, and the thickness reached the normal level. The content of ß-carotene and retinoids in the liver of chitosan and ß-carotene co-treated group increased by 46.75 % and 20.69 %, respectively, compared to the ß-carotene group. Chitosan and ß-carotene supplement suppressed the expressions of Bax, Calpain2, Caspase3, NF-κB, TNF-α, IL-6, and IL-1ß, and promoted the up-regulation of Bcl2. Chitosan and ß-carotene interventions remarkably contributed to the content of SCFAs and enhanced the abundance of Ruminococcaceae, Rikenellaceae, Odoribacteraceae and Helicobacteraceae. Correlation analysis demonstrated a strong association between gut microbiota and improvement in retinitis pigmentosa. This study will provide a reference for the study of the gut-eye axis.

Thermal performance and experimental analysis of stainless steel flat plate solar collector with full-flow channels.

The thermal performance of a flat plate solar collector (FPSC) is a critical indicator that depends on the environment, operational parameters, and dimensions. This study examines the impact of size on thermal performance improvement mechanisms. Firstly, numerical simulation models are introduced as the foundation for optimization research. This involves analyzing the flow resistance of microchannels and defining their structural parameters. Furthermore, experimental tests were conducted on a stainless steel flat plate solar collector (S/S FPSC) with the best design parameters to validate the accuracy of the mathematical model during the design phase. The results indicate that increasing the width of the microchannel and the height of corrugations can effectively enhance the thermal performance of the S/S FPSC. The momentary efficiency is projected to reach a remarkable 86.10% under ideal circumstances. Additionally, a mathematical expression was proposed to establish the relationship between the surrounding conditions and the momentary efficiency of the S/S FPSC. Moreover, the microchannel comprises S/S material, maintaining a homogeneous temperature distribution to maximize heat absorption. The use of stainless steel also extends the lifespan of the FPSC.

Analysis of the interaction-length dependence of frequency stability in an iodine-stabilized Nd:YAG laser.

We report a numerical simulation and an experimental study on the interaction-length dependence of frequency stability in an iodine-stabilized neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. A saturation spectroscopy model was used in the simulation to calculate the interaction-length dependence of the linewidth and signal-to-noise ratio of the iodine saturation spectrum. We determined that 2 m was the optimal interaction length for laser-frequency stabilization. We confirmed the simulation results by performing modulation transfer spectroscopy and laser-frequency stabilization using 45-cm- and 2-m-long iodine cells and multipass configurations. The results of this study are useful for designing compact and highly stable iodine-stabilized lasers.

Associations between the cause of amblyopia and pre-treatment contrast sensitivity, stereoacuity, fixation, and nystagmus.

Purpose: To explore the association between the cause of amblyopia and pre-treatment contrast sensitivity, stereoacuity, fixation and nystagmus. Design: Retrospective cohort study. Methods: A retrospective review was conducted for 3408 patients with amblyopia who had not yet started amblyopia treatment utilizing a large amblyopia patient database maintained at Zhongshan Ophthalmic Centre. Six amblyogenic factor subtypes were identified: anisometropia, isoametropia, strabismus, anisometropia and strabismus, monocular visual deprivation, and binocular visual deprivation amblyopia. Monocular best corrected visual acuity (BCVA), the contrast sensitivity function (CSF), fixation, and stereopsis were compared between the subtypes before and after propensity score matching (PSM) for age and sex. Results: The two deprivation groups had poorer BCVA and CSF than the other groups. There were no systematic differences in CSF between the non-deprivation groups. Nystagmus was more common in the bilateral amblyopia groups compared to the monocular amblyopia groups. Eccentric fixation was uncommon with the exception of the anisometropia and strabismus group which had an eccentric fixation rate of 20%. Distance stereoacuity measured without monocular cues was absent for almost all patients. The results were consistent when analyzed using PSM. Conclusion: Visual deprivation causes more severe amblyopia than other amblyogenic factors. For non-deprivation amblyopia subtypes, individual differences such as variation in the severity of the amblyogenic factor might be more important in determining pre-treatment vision than whether amblyopia was caused by refractive error, strabismus or both.

A new nomogram to predict in-hospital mortality in patients with acute decompensated chronic heart failure and diabetes after 48 Hours of Intensive Care Unit.

BACKGROUND: The study set out to develop an accurate and clinically valuable prognostic nomogram to assess the risk of in-hospital death in patients with acute decompensated chronic heart failure (ADCHF) and diabetes. METHODS: We extracted clinical data of patients diagnosed with ADCHF and diabetes from the Medical Information Mart for Intensive Care III database. Risk variables were selected utilizing least absolute shrinkage and selection operator regression analysis, and were included in multivariate logistic regression and presented in nomogram. bootstrap was used for internal validation. The discriminative power and predictive accuracy of the nomogram were estimated using the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: Among 867 patients with ADCHF and diabetes, In-hospital death occurred in 81 (9.3%) patients. Age, heart rate, systolic blood pressure, red blood cell distribution width, shock, ß-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, assisted ventilation, and blood urea nitrogen were brought into the nomogram model. The calibration curves suggested that the nomogram was well calibrated. The AUC of the nomogram was 0.873 (95% CI: 0.834-0.911), which was higher that of the Simplified Acute Physiology Score II [0.761 (95% CI: 0.711-0.810)] and sequential organ failure assessment score [0.699 (95% CI: 0.642-0.756)], and Guidelines-Heart Failure score [0.782 (95% CI: 0.731-0.835)], indicating that the nomogram had better ability to predict in-hospital mortality. In addition, the internally validated C-index was 0.857 (95% CI: 0.825-0.891), which again verified the validity of this model. CONCLUSIONS: This study constructed a simple and accurate nomogram for predicting in-hospital mortality in patients with ADCHF and diabetes, especially in those who admitted to the intensive care unit for more than 48 hours, which contributed clinicians to assess the risk and individualize the treatment of patients, thereby reducing in-hospital mortality.

Preparation of Peptoid Antifreeze Agents and Their Structure-Property Relationship.

The development of nontoxic and efficient antifreeze agents for organ cryopreservation is crucial. However, the research remains highly challenging. In this study, we designed and synthesized a series of peptoid oligomers using the solid-phase submonomer synthesis method by mimicking the amphiphilic structures of antifreeze proteins (AFPs). The obtained peptoid oligomers showed excellent antifreeze properties, reducing the ice crystal growth rate and inhibiting ice recrystallization. The effects of the hydrophobicity and sequence of the peptoid side chains were also studied to reveal the structure-property relationship. The prepared peptoid oligomers were detected as non-cytotoxic and considered to be useful in the biological field. We hope that the peptoid oligomers presented in this study can provide effective strategies for the design of biological cryoprotectants for organ preservation in the future.

Cost-Effectiveness of First-Line Atezolizumab versus Chemotherapy in Non-Small-Cell Lung Cancer Patients Ineligible for Platinum-Containing Regimens.

Purpose: The IPSOS study provided evidence supporting the efficacy and tolerability of first-line atezolizumab compared to single-agent chemotherapy for non-small-cell lung cancer (NSCLC) patients ineligible for treatment with a platinum-containing regimen. This study aimed to assess the cost-effectiveness of atezolizumab specifically in this population, considering the perspective of the Chinese healthcare system. Patients and Methods: In this analysis, a three-state Markov model was utilized. The survival data were derived from the IPSOS clinical trial. Direct medical costs and utility values were collected from national authoritative database and published literature. The primary outcomes were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). To ensure the robustness of our model, both one-way and probabilistic sensitivity analyses were conducted. Results: Atezolizumab monotherapy led to an increase in costs of $4139.23 compared to single-agent chemotherapy. Additionally, it resulted in a gain of 0.14 QALYs, leading to an ICER of $29,365.79 per QALY, which was below the willingness-to-pay threshold of $36,066 per QALY used in the model. One-way sensitivity analyses revealed cost of atezolizumab and utility of progressive disease (PD) as major influencing factors for ICER. Furthermore, probabilistic sensitivity analyses confirmed our base-case results. Conclusion: From the perspective of the Chinese healthcare system, atezolizumab emerges as a cost-effective choice for the first-line treatment of NSCLC patients ineligible for platinum-based chemotherapy.

Reversal of the concreteness effect can be detected in the natural speech of older adults with amnestic, but not non-amnestic, mild cognitive impairment.

INTRODUCTION: Patients with Alzheimer's disease present with difficulty in lexical retrieval and reversal of the concreteness effect in nouns. Little is known about the phenomena before the onset of symptoms. We anticipate early linguistic signs in the speech of people who suffer from amnestic mild cognitive impairment (MCI). Here, we report the results of a corpus-linguistic approach to the early detection of cognitive impairment. METHODS: One hundred forty-eight English-speaking Singaporeans provided natural speech data, on topics of their choice; 74 were diagnosed with single-domain MCI (38 amnestic, 36 non-amnestic), 74 cognitively healthy. The recordings yield 267,310 words, which are tagged for parts of speech. We calculate the per-minute word counts and concreteness scores of all tagged words, nouns, and verbs in the dataset. RESULTS: Compared to controls, subjects with amnestic MCI produce fewer but more abstract nouns. Verbs are not affected. DISCUSSION: Slower retrieval of nouns and the reversal of the concreteness effect in nouns are manifested in natural speech and can be detected early through corpus-based analysis. Highlights: Reversal of the concreteness effect is manifested in patients with Alzheimer's disease (AD) and semantic dementia.The paper reports a corpus-based analysis of natural speech by people with amnestic and non-amnestic mild cognitive impairment (MCI) and cognitively healthy controls.People with amnestic MCI produce fewer and more abstract nouns than people with non-amnestic MCI and healthy controls. Verbs appear to be unaffected.The imageability problem can be detected in natural everyday speech by people with amnestic MCI, which carries a higher risk of conversion to AD.

A reference-grade genome of the xerophyte Ammopiptanthus mongolicus sheds light on its evolution history in legumes and drought-tolerance mechanisms.

Plants that grow in extreme environments represent unique sources of stress-resistance genes and mechanisms. Ammopiptanthus mongolicus (Leguminosae) is a xerophytic evergreen broadleaf shrub native to semi-arid and desert regions; however, its drought-tolerance mechanisms remain poorly understood. Here, we report the assembly of a reference-grade genome for A. mongolicus, describe its evolutionary history within the legume family, and examine its drought-tolerance mechanisms. The assembled genome is 843.07 Mb in length, with 98.7% of the sequences successfully anchored to the nine chromosomes of A. mongolicus. The genome is predicted to contain 47 611 protein-coding genes, and 70.71% of the genome is composed of repetitive sequences; these are dominated by transposable elements, particularly long-terminal-repeat retrotransposons. Evolutionary analyses revealed two whole-genome duplication (WGD) events at 130 and 58 million years ago (mya) that are shared by the genus Ammopiptanthus and other legumes, but no species-specific WGDs were found within this genus. Ancestral genome reconstruction revealed that the A. mongolicus genome has undergone fewer rearrangements than other genomes in the legume family, confirming its status as a "relict plant". Transcriptomic analyses demonstrated that genes involved in cuticular wax biosynthesis and transport are highly expressed, both under normal conditions and in response to polyethylene glycol-induced dehydration. Significant induction of genes related to ethylene biosynthesis and signaling was also observed in leaves under dehydration stress, suggesting that enhanced ethylene response and formation of thick waxy cuticles are two major mechanisms of drought tolerance in A. mongolicus. Ectopic expression of AmERF2, an ethylene response factor unique to A. mongolicus, can markedly increase the drought tolerance of transgenic Arabidopsis thaliana plants, demonstrating the potential for application of A. mongolicus genes in crop improvement.

TRPC4 aggravates hypoxic pulmonary hypertension by promoting pulmonary endothelial cell apoptosis.

Pulmonary hypertension (PH) is a devastating disease that lacks effective treatment options and is characterized by severe pulmonary vascular remodeling. Pulmonary arterial endothelial cell (PAEC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension. Canonical transient receptor potential (TRPC) channels, a family of Ca2+-permeable channels, play an important role in various diseases. However, the effect and mechanism of TRPCs on PH development have not been fully elucidated. Among the TRPC family members, TRPC4 expression was markedly upregulated in PAECs from hypoxia combined with SU5416 (HySu)-induced PH mice and monocrotaline (MCT)-treated PH rats, as well as in hypoxia-exposed PAECs, suggesting that TRPC4 in PAECs may participate in the occurrence and development of PH. In this study, we aimed to investigate whether TRPC4 in PAECs has an aggravating effect on PH and elucidate the molecular mechanisms. We observed that hypoxia treatment promoted PAEC apoptosis through a caspase-12/endoplasmic reticulum stress (ERS)-dependent pathway. Knockdown of TRPC4 attenuated hypoxia-induced apoptosis and caspase-3/caspase-12 activity in PAECs. Accordingly, adeno-associated virus (AAV) serotype 6-mediated pulmonary endothelial TRPC4 silencing (AAV6-Tie-shRNA-TRPC4) or TRPC4 antagonist suppressed PH progression as evidenced by reduced right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, PAEC apoptosis and reactive oxygen species (ROS) production. Mechanistically, unbiased RNA sequencing (RNA-seq) suggested that TRPC4 deficiency suppressed the expression of the proapoptotic protein sushi domain containing 2 (Susd2) in hypoxia-exposed mouse PAECs. Moreover, TRPC4 activated hypoxia-induced PAEC apoptosis by promoting Susd2 expression. Therefore, inhibiting TRPC4 ameliorated PAEC apoptosis and hypoxic PH in animals by repressing Susd2 signaling, which may serve as a therapeutic target for the management of PH.

Self-Assembly Study of Block Copolypeptoids in Response to pH and Temperature Stimulation.

Polypeptoids with well-designed structures have the ability to self-assemble into nanomaterials, which have wide potential applications. In this study, a series of diblock copolypeptoids were synthesized via ring-opening polymerization followed by click chemistry and exhibited both temperature and pH stimulation responsiveness. Under specific temperature and pH conditions, the responsive blocks in the copolypeptoids became hydrophobic and aggregated to form micelles. The self-assembly process was monitored using the UV-Vis and DLS methods, which suggested the reversible transition of free molecules to micelles and bigger aggregates upon instituting temperature and pH changes. By altering the length and proportion of each block, the copolypeptoids displayed varying self-assembly characteristics, and the transition temperature could be tuned. With good biocompatibility, stability, and no cytotoxicity, the polypeptoids reported in this study are expected to be applied as bionanomaterials in fields including drug delivery, tissue engineering, and intelligent biosensing.