Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2.

The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism underlying this process has remained elusive. In this study, we performed a genome-wide CRISPR/Cas9 screen, revealing that ZSWIM8 as the substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated STAT2 degradation. Genetic depletion of ZSWIM8 and CUL3 substantially impeded NS5-mediated STAT2 degradation. Biochemical analysis illuminated that NS5 enhances the interaction between STAT2 and the ZSWIM8-CUL3 E3 ligase complex, thereby facilitating STAT2 ubiquitination. Moreover, ZSWIM8 knockout endowed A549 and Huh7 cells with partial resistance to ZIKV infection and protected cells from the cytopathic effects induced by ZIKV, which was attributed to the restoration of STAT2 levels and the activation of IFN signaling. Subsequent studies in a physiologically relevant model, utilizing human neural progenitor cells, demonstrated that ZSWIM8 depletion reduced ZIKV infection, resulting from enhanced IFN signaling attributed to the sustained levels of STAT2. Our findings shed light on the role of ZIKV NS5, serving as the scaffold protein, reprograms the ZSWIM8-CUL3 E3 ligase complex to orchestrate STAT2 proteasome-dependent degradation, thereby facilitating evasion of IFN antiviral signaling. Our study provides unique insights into ZIKV-host interactions and holds promise for the development of antivirals and prophylactic vaccines.

Hierarchical functional differences between gyri and sulci at different scales.

Gyri and sulci are 2 fundamental cortical folding patterns of the human brain. Recent studies have suggested that gyri and sulci may play different functional roles given their structural and functional heterogeneity. However, our understanding of the functional differences between gyri and sulci remains limited due to several factors. Firstly, previous studies have typically focused on either the spatial or temporal domain, neglecting the inherently spatiotemporal nature of brain functions. Secondly, analyses have often been restricted to either local or global scales, leaving the question of hierarchical functional differences unresolved. Lastly, there has been a lack of appropriate analytical tools for interpreting the hierarchical spatiotemporal features that could provide insights into these differences. To overcome these limitations, in this paper, we proposed a novel hierarchical interpretable autoencoder (HIAE) to explore the hierarchical functional difference between gyri and sulci. Central to our approach is its capability to extract hierarchical features via a deep convolutional autoencoder and then to map these features into an embedding vector using a carefully designed feature interpreter. This process transforms the features into interpretable spatiotemporal patterns, which are pivotal in investigating the functional disparities between gyri and sulci. We evaluate the proposed framework on Human Connectome Project task functional magnetic resonance imaging dataset. The experiments demonstrate that the HIAE model can effectively extract and interpret hierarchical spatiotemporal features that are neuroscientifically meaningful. The analyses based on the interpreted features suggest that gyri are more globally activated, whereas sulci are more locally activated, demonstrating a distinct transition in activation patterns as the scale shifts from local to global. Overall, our study provides novel insights into the brain's anatomy-function relationship.

Structural Complexities in Sodium Ion Conductive Antiperovskite Revealed by Cryogenic Transmission Electron Microscopy.

We use low-dose cryogenic transmission electron microscopy (cryo-TEM) to investigate the atomic-scale structure of antiperovskite Na2NH2BH4 crystals by preserving the room-temperature cubic phase and carefully monitoring the electron dose. Via quantitative analysis of electron beam damage using selected area electron diffraction, we find cryogenic imaging provides 6-fold improvement in beam stability for this solid electrolyte. Cryo-TEM images obtained from flat crystals revealed the presence of a new, long-range-ordered supercell with a cubic phase. The supercell exhibits doubled unit cell dimensions of 9.4 Å × 9.4 Å as compared to the cubic lattice structure revealed by X-ray crystallography of 4.7 Å × 4.7 Å. The comparison between the experimental image and simulated potential map indicates the origin of the supercell is a vacancy ordering of sodium atoms. This work demonstrates the potential of using cryo-TEM imaging to study the atomic-scale structure of air- and electron-beam-sensitive antiperovskite-type solid electrolytes.

An interpretable Bayesian clustering approach with feature selection for analyzing spatially resolved transcriptomics data.

Recent breakthroughs in spatially resolved transcriptomics (SRT) technologies have enabled comprehensive molecular characterization at the spot or cellular level while preserving spatial information. Cells are the fundamental building blocks of tissues, organized into distinct yet connected components. Although many non-spatial and spatial clustering approaches have been used to partition the entire region into mutually exclusive spatial domains based on the SRT high-dimensional molecular profile, most require an ad hoc selection of less interpretable dimensional-reduction techniques. To overcome this challenge, we propose a zero-inflated negative binomial mixture model to cluster spots or cells based on their molecular profiles. To increase interpretability, we employ a feature selection mechanism to provide a low-dimensional summary of the SRT molecular profile in terms of discriminating genes that shed light on the clustering result. We further incorporate the SRT geospatial profile via a Markov random field prior. We demonstrate how this joint modeling strategy improves clustering accuracy, compared with alternative state-of-the-art approaches, through simulation studies and 3 real data applications.

Accurate and affordable detection of rifampicin and isoniazid resistance in Tuberculosis sputum specimens by multiplex PCR-multiple probes melting analysis.

BACKGROUND: Escalating cases of multidrug-resistant tuberculosis (MDR-TB) pose a major challenge to global TB control efforts, necessitating innovative diagnostics to empower decentralized detection of gene mutations associated with resistance to rifampicin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis (M. tuberculosis) in resource-constrained settings. METHODS: Combining multiplex fluorescent PCR and Multiple Probes Melting Analysis, we identified mutations in the rpoB, katG, ahpC and inhA genes from sputum specimens. We first constructed a reference plasmid library comprising 40 prevalent mutations in the target genes' resistance determining regions and promoters, serving as positive controls. Our assay utilizes a four-tube asymmetric PCR method with specifically designed molecular beacon probes, enabling simultaneous detection of all 40 mutations. We evaluated the assay's effectiveness using DNA isolated from 50 clinically confirmed M. tuberculosis sputum specimens, comparing our results with those obtained from Sanger sequencing and retrospective validation involving bacteriological culture and phenotypic drug susceptibility testing (pDST). We also included the commercial Xpert MTB/RIF assay for accuracy comparison. RESULTS: Our data demonstrated remarkable sensitivity in detecting resistance to RIF and INH, achieving values of 93.33% and 95.24%, respectively, with a specificity of 100%. The concordance between our assay and pDST was 98.00%. Furthermore, the accuracy of our assay was comparable to both Sanger sequencing and the Xpert assay. Importantly, our assay boasts a 4.2-h turnaround time and costs only $10 per test, making it an optimal choice for peripheral healthcare settings. CONCLUSION: These findings highlight our assay's potential as a promising tool for rapidly, accurately, and affordably detecting MDR-TB.

Association between the trajectory of ideal cardiovascular health metrics and incident chronic kidney disease among 27,635 older adults in northern China-a prospective cohort study.

BACKGROUND: There is a lack of relevant studies evaluating the long-term impact of cardiovascular health factor (CVH) metrics on chronic kidney disease (CKD). OBJECTIVE: This study investigates the long-term change in CVH metrics in older people and explores the relationship between CVH metrics trajectory and CKD. METHODS: In total, 27,635 older people aged over 60 from the community-based Tianjin Chronic Kidney Disease Cohort study were enrolled. The participants completed five annual physical examinations between January 01, 2014, and December 31, 2018, and a subsequent follow-up between January 01, 2019, and December 31, 2021. CVH metrics trajectories were established by the group-based trajectory model to predict CKD risk. The relationships between baseline CVH, CVH change (ΔCVH), and CKD risk were also explored by logistic regression and restricted cubic spline regression model. In addition, likelihood ratio tests were used to compare the goodness of fit of the different models. RESULTS: Six distinct CVH metrics trajectories were identified among the participants: low-stable (11.19%), low-medium-stable (30.58%), medium-stable (30.54%), medium-high-decreased (5.46%), medium-high-stable (18.93%), and high-stable (3.25%). After adjustment for potential confounders, higher CVH metrics trajectory was associated with decreased risk of CKD (P for trend < 0.001). Comparing the high-stable with the low-stable group, the risk of CKD decreased by 46%. All sensitivity analyses, including adjusting for baseline CVH and removing each CVH component from the total CVH, produced consistent results. Furthermore, the likelihood ratio test revealed that the model established by the CVH trajectory fit better than the baseline CVH and Δ CVH. CONCLUSION: The higher CVH metrics trajectory and improvement of CVH metrics were associated with decreased risk of CKD. This study emphasized the importance of improving CVH to achieve primary prevention of CKD in older people.

Unraveling the relationship between high-sensitivity C-reactive protein and frailty: evidence from longitudinal cohort study and genetic analysis.

BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

Auxiliary occlusal devices for IO scanning in a complete digital workflow of implant-supported crowns: a randomized controlled trial.

OBJECTIVES: To compare the crown accuracy and time efficiency of a complete digital workflow, utilizing an auxiliary occlusal device and IO scanning, with a conventional workflow, for multiple implant-supported single crowns. MATERIALS AND METHODS: 24 patients with two adjacent posterior implants were included. 12 patients were randomly assigned to digital workflow group, involving intra-oral scanning with an auxiliary occlusal device and manufacture of customized abutments and zirconia single crowns (test group). The other 12 were assigned to the conventional workflow (control group), involving conventional impression and CAD-CAM crowns based on stone casts. Crown scanning was done before and after clinical adjustment using an intraoral scanner. Two 3D digital models were overlapped to assess dimension changes. Chair-side and laboratory times for the entire workflow were recorded and a linear mixed model and Independent-sample t tests were used for the statistical analysis. RESULTS: The maximum occlusal deviation was 279.67 ± 112.17 µm and 479.59 ± 203.63 µm in the test and control group, respectively (p < 0.001). The sizes of the occlusion adjustment areas were 12.12 ± 10.51 mm2 and 25.12 ± 14.14 mm2 in the test and control groups, respectively (p = 0.013). The mean laboratory time was 46.08 ± 5.45 and 105.92 ± 6.10 min in the test and control groups, respectively (p < 0.001).The proximal contact adjustment and mean chair-side time showed no statistically significant difference between two groups. CONCLUSIONS: A digital workflow for two implants-supported single crowns using an auxiliary device required fewer occlusal crown adjustments, and less laboratory time compared to conventional workflow. CLINICAL RELEVANCE: The use of auxiliary occlusal devices in IOS enhances the accuracy of virtual maxillomandibular relationship in extended edentulous spans. Consequently, employing a digital workflow for multiple implants-supported crowns using IO scanning and an auxiliary occlusal device proves to be a feasible, accurate and efficient approach.

Digital registration versus cone-beam computed tomography for evaluating implant position: a prospective cohort study.

BACKGROUND: Postoperative cone-beam computed tomography (CBCT) examination is considered a reliable method for clinicians to assess the positions of implants. Nevertheless, CBCT has drawbacks involving radiation exposure and high costs. Moreover, the image quality can be affected by artifacts. Recently, some literature has mentioned a digital registration method (DRM) as an alternative to CBCT for evaluating implant positions. The aim of this clinical study was to verify the accuracy of the DRM compared to CBCT scans in postoperative implant positioning. MATERIALS AND METHODS: A total of 36 patients who received anterior maxillary implants were included in this clinical study, involving a total of 48 implants. The study included 24 patients in the single implant group and 12 patients in the dual implant group. The postoperative three-dimensional (3D) positions of implants were obtained using both CBCT and DRM. The DRM included three main steps. Firstly, the postoperative 3D data of the dentition and intraoral scan body (ISB) was obtained through the intraoral scan (IOS). Secondly, a virtual model named registration unit which comprised an implant replica and a matching ISB was created with the help of a lab scanner and reverse engineering software. Thirdly, by superimposing the registration unit and IOS data, the postoperative position of the implant was determined. The accuracy of DRM was evaluated by calculating the Root Mean Square (RMS) values after superimposing the implant positions obtained from DRM with those from postoperative CBCT. The accuracy of DRM was compared between the single implant group and the dual implant group using independent sample t-tests. The superimposition deviations of CBCT and IOS were also evaluated. RESULTS: The overall mean RMS was 0.29 ± 0.05 mm. The mean RMS was 0.30 ± 0.03 mm in the single implant group and 0.29 ± 0.06 mm in the dual implant group, with no significant difference (p = 0.27). The overall registration accuracy of the IOS and CBCT data ranged from 0.14 ± 0.05 mm to 0.21 ± 0.08 mm. CONCLUSION: In comparison with the 3D implant positions obtained by CBCT, the implant positions located by the DRM showed clinically acceptable deviation ranges. This method can be used in single and dual implant treatments to assess the implant positions.

Crown adjustment and chairside efficiency of single-unit restorations fabricated from immediate and staged impressions using a digital workflow for posterior implants.

PURPOSE: This is a clinical study to compare immediate and staged impression methods in a complete digital workflow for single-unit implants in the posterior area. MATERIALS AND METHODS: Sixty patients requiring single-unit implant crowns were enrolled. Forty patients were assigned to the test group, immediate digital impression after implant surgery with crown delivery 4 months later. The remaining 20 patients were assigned to the control group, staged digital impressions 4 months after implant surgery, and crown delivery 1 month later. Both workflows involved free-model CAD-CAM crown fabrications. The crowns were scanned before and after clinical adjustment using an intraoral scanner (TRIOS Color; 3Shape). Two 3D digital models were trimmed and superimposed to evaluate the dimensional changes using Geomagic Control software. Chairside times for the entire workflow were recorded. Kruskal-Wallis was performed to compare crown adjustments between two groups, while One-way ANOVA was used to compare chairside time durations between the test and control groups. RESULTS: All crowns were delivered without refabrication. The average maximum occlusion adjustment of crowns was -353.2 ± 207.1 µm in the test group and -212.7 ± 150.5 µm in the control group (p = 0.02). The average area of occlusal adjustment, measured as an area of deviation larger than 100 µm, was 14.8 ± 15.3 and 8.4 ± 8.1 mm2 in the test and control groups, respectively (p = 0.056). There were no significant differences in the mesial and distal contact adjustment amounts, or the maximum deviations of the proximal area, between the two groups. The mean chair-side time was 50.25 ± 13.48 and 51.20 ± 5.34 min in the test and control groups, respectively (p = 0.763). CONCLUSIONS: The immediate impression method in the digital workflow for single-unit implants required more occlusal adjustments of crowns but showed similar chairside times compared to the staged impression method.

Impact of vertical alveoloplasty on changes in keratinized mucosa width following full-arch immediate implant placement and rehabilitations: A prospective case series.

PURPOSE: This prospective case series aimed to investigate the effect of vertical alveoloplasty on the changes in keratinized mucosa width (KMW) following full-arch immediate implant placement and rehabilitation. MATERIALS AND METHODS: A total of 17 potential edentulous patients were enrolled and received implant placement and full-arch implant-supported immediate rehabilitations. The main outcome was to analyze the effect of vertical alveoloplasty on the changes in KMW. The amount of vertical alveoloplasty during implant surgery as well as the changes in KMW at buccal aspects from the day of surgery to 6 months post-surgery were recorded on the implant-level using a periodontal probe. The secondary outcome was to analyze the other possible factors that affected the changes in KMW. The included factors were the initial KMW, the distribution of implants in the maxilla and mandible, the distribution of implants in the anterior and posterior regions, the distribution of implants in extraction sockets and healed ridges, and gender. Mann-Whitney non-parametric tests and multiple linear regression adjusted by generalized estimating equations (GEE) were used to statistically analyze the data. RESULTS: A total of 121 implant positions were analyzed. The KMW was 4.1± 2.0 mm on the day of the surgery and 4.1± 1.7 mm 6 months post-surgery. The mean changes in KMW following 6 months were -0.1± 1.6 mm (p = 0.824). From the results of GEE, the vertical amount of alveoloplasty had no significant effect on changes in KMW. Both initial KMW and the distribution of implants in the anterior and posterior regions had significant impacts on the changes in KMW (p < 0.0001). CONCLUSION: The amount of vertical alveoloplasty during implant surgery has no significant impact on the KMW. The KMW remained stable from baseline to 6 months after alveoloplasty, implant placement, and immediate rehabilitations in potential edentulous arches. The initial KMW and the distribution of implants in the anterior and posterior regions were the possible factors affecting changes in KMW.

Cuproptosis-Associated lncRNA Gene Signature Establishes New Prognostic Profile and Predicts Immunotherapy Response in Endometrial Carcinoma.

Uterine corpus endometrial carcinoma (UCEC), a prevalent kind of cancerous tumor in female reproductive system that has a dismal prognosis in women worldwide. Given the very limited studies of cuproptosis-related lncRNAs (CRLs) in UCEC. Our purpose was to construct a prognostic profile based on CRLs and explore its assess prognostic value in UCEC victims and its correlation with the immunological microenvironment. METHODS: 554 UCEC tumor samples and 23 normal samples' RNA-seq statistics and clinical details were compiled from data in the TCGA database. CRLs were obtained using Pearson correlation analysis. Using LASSO Cox regression, multivariate Cox regression, and univariate Cox regression analysis, six CRLs are confirmed to develop a risk prediction model at last.We identified two main molecular subtypes and observed that multilayer CRLs modifications were related to patient clinicopathological features, prognosis, and tumor microenvironment (TME) cell infiltration characteristics, and then we verified the prognostic hallmark of UCEC and examined its immunological landscape.Finally, using qRT-PCR, model hub genes' expression patterns were confirmed. RESULTS: A unique CRL signature was established by the combination of six differently expressed CRLs that were highly linked with the prognosis of UCEC patients. According to their CRLs signatures, the patients were divided into two groups: the low-risk and the high-risk groups. Compared to individuals at high risk, patients at low risk had higher survival rates (p < 0.001). Additionally, Cox regression reveals that the profiles of lncRNAs linked to cuproptosis may independently predict prognosis in UCEC patients. The 1-, 3-, and 5-year risks' respective receiver operating characteristics (ROC) exhibited AUC values of 0.778, 0.810, and 0.854. Likewise, the signature could predict survival in different groups based on factors like stage, age, and grade, among others. Further investigation revealed differences between the different risk score groups in terms of drug sensitivity,immune cell infiltration,tumor mutation burden (TMB) score and microsatellite instability (MSI) score. Compared to the group of high risk, the low-risk group had greater rates of TMB and MSI. Results from qRT-PCR revealed that in UCEC vs normal tissues, AC026202.2, NRAV, AC079466.2, and AC090617.5 were upregulated,while LINC01545 and AL450384.1 were downregulated. CONCLUSIONS: Our research clarified the relationship between CRLs signature and the immunological profile and prognosis of UCEC.This signature will establish the framework for future investigations into the endometrial cancer CRLs mechanism as well as the exploitation of new diagnostic tools and new therapeutic.

Effects of Electric Field on Chemical Looping Combustion: A DFT Study of CO Oxidation on CuO (111) Surface.

Chemical looping combustion (CLC) is a promising and novel technology for carbon dioxide (CO2) capture with a relatively low energy consumption and cost. CuO, one of the most attractive oxygen carriers (OCs) for carbon dioxide (CO) oxidation, suffers from sintering and agglomeration during the reduction process. Applying an electric field (EF) may promote the CO oxidation process on the CuO surface, which could mitigate sintering and agglomeration by decreasing operating temperatures with negligible combustion efficiency loss. This study performs density functional theory (DFT) simulations to investigate the effects of EF on the oxidation of CO on the CuO (111) surface. The results indicate that both the orientation and strength of the EF can significantly affect the oxidation characteristics of CO on the CuO (111) surface such as total reaction energy, energy barriers of reactions, CO adsorption, and CO2 desorption. For the first time, this study reveals the role of EF in enhancing CO oxidation through CLC processes via first-principle calculations. Such findings could provide new strategies to improve the performance of CLC processes.

Bayesian hidden mark interaction model for detecting spatially variable genes in imaging-based spatially resolved transcriptomics data.

Recent technology breakthroughs in spatially resolved transcriptomics (SRT) have enabled the comprehensive molecular characterization of cells whilst preserving their spatial and gene expression contexts. One of the fundamental questions in analyzing SRT data is the identification of spatially variable genes whose expressions display spatially correlated patterns. Existing approaches are built upon either the Gaussian process-based model, which relies on ad hoc kernels, or the energy-based Ising model, which requires gene expression to be measured on a lattice grid. To overcome these potential limitations, we developed a generalized energy-based framework to model gene expression measured from imaging-based SRT platforms, accommodating the irregular spatial distribution of measured cells. Our Bayesian model applies a zero-inflated negative binomial mixture model to dichotomize the raw count data, reducing noise. Additionally, we incorporate a geostatistical mark interaction model with a generalized energy function, where the interaction parameter is used to identify the spatial pattern. Auxiliary variable MCMC algorithms were employed to sample from the posterior distribution with an intractable normalizing constant. We demonstrated the strength of our method on both simulated and real data. Our simulation study showed that our method captured various spatial patterns with high accuracy; moreover, analysis of a seqFISH dataset and a STARmap dataset established that our proposed method is able to identify genes with novel and strong spatial patterns.

Global, regional, and national burden of atrial fibrillation/flutter related to metabolic risks over three decades: estimates from the global burden of disease study 2019.

AIMS: Atrial fibrillation/atrial flutter (AF/AFL) remains a significant public health concern on a global scale, with metabolic risks playing an increasingly prominent role. This study aimed to investigate comprehensive epidemiological data and trends concerning the metabolic risks related-AF/AFL burden based on the data from the Global Burden of Disease study in 2019. METHODS AND RESULTS: The analysis of disease burden focused on numbers, age-standardized rates of deaths, disability-adjusted life years (DALYs), and estimated annual percentage change, while considering factors of age, sex, sociodemographic index (SDI), and locations. In 2019, there was a culmination of 137 179 deaths and 4 099 146 DALYs caused by metabolic risks related-AF/AFL worldwide, with an increase of 162.95% and 120.30%, respectively from 1990. High and high-middle SDI regions predominantly carried the burden of AF/AFL associated with metabolic risks, while a shift towards lower SDI regions had been occurring. Montenegro had the highest recorded death rate (7.6 per 100 000) and DALYs rate (146.3 per 100 000). An asymmetrically inverted V-shaped correlation was found between SDI and deaths/DALYs rates. Moreover, females and the elderly exhibited higher AF/AFL burdens, and young adults (over 40 years old) also experienced an annual increase. CONCLUSION: The global AF/AFL burden related to metabolic risks has significantly increased over the past three decades, with considerable spatiotemporal, gender-based, and age-related heterogeneity. These findings shed valuable light on the trends in the burden of metabolic risks related-AF/AFL and offered insights into corresponding strategies.

MGIML: Cancer Grading With Incomplete Radiology-Pathology Data via Memory Learning and Gradient Homogenization.

Taking advantage of multi-modal radiology-pathology data with complementary clinical information for cancer grading is helpful for doctors to improve diagnosis efficiency and accuracy. However, radiology and pathology data have distinct acquisition difficulties and costs, which leads to incomplete-modality data being common in applications. In this work, we propose a Memory- and Gradient-guided Incomplete Modal-modal Learning (MGIML) framework for cancer grading with incomplete radiology-pathology data. Firstly, to remedy missing-modality information, we propose a Memory-driven Hetero-modality Complement (MH-Complete) scheme, which constructs modal-specific memory banks constrained by a coarse-grained memory boosting (CMB) loss to record generic radiology and pathology feature patterns, and develops a cross-modal memory reading strategy enhanced by a fine-grained memory consistency (FMC) loss to take missing-modality information from well-stored memories. Secondly, as gradient conflicts exist between missing-modality situations, we propose a Rotation-driven Gradient Homogenization (RG-Homogenize) scheme, which estimates instance-specific rotation matrices to smoothly change the feature-level gradient directions, and computes confidence-guided homogenization weights to dynamically balance gradient magnitudes. By simultaneously mitigating gradient direction and magnitude conflicts, this scheme well avoids the negative transfer and optimization imbalance problems. Extensive experiments on CPTAC-UCEC and CPTAC-PDA datasets show that the proposed MGIML framework performs favorably against state-of-the-art multi-modal methods on missing-modality situations.

A cell therapy approach based on iPSC-derived midbrain organoids for the restoration of motor function in a Parkinson's disease mouse model.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and loss of DA transmission in the striatum, thus making cell transplantation an effective treatment strategy. Here, we develop a cellular therapy based on induced pluripotent stem cell (iPSC)-derived midbrain organoids. By transplanting midbrain organoid cells into the striatum region of a 6-OHDA-lesioned PD mouse model, we found that the transplanted cells survived and highly efficiently differentiated into DA neurons. Further, using a dopamine sensor, we observed that the differentiated human DA neurons could efficiently release dopamine and were integrated into the neural network of the PD mice. Moreover, starting from four weeks after transplantation, the motor function of the transplanted mice could be significantly improved. Therefore, cell therapy based on iPSC-derived midbrain organoids can be a potential strategy for the clinical treatment of PD.

Frequency-specific functional difference between gyri and sulci in naturalistic paradigm fMRI.

Disentangling functional difference between cortical folding patterns of gyri and sulci provides novel insights into the relationship between brain structure and function. Previous studies using resting-state functional magnetic resonance imaging (rsfMRI) have revealed that sulcal signals exhibit stronger high-frequency but weaker low-frequency components compared to gyral ones, suggesting that gyri may serve as functional integration centers while sulci are segregated local processing units. In this study, we utilize naturalistic paradigm fMRI (nfMRI) to explore the functional difference between gyri and sulci as it has proven to record stronger functional integrations compared to rsfMRI. We adopt a convolutional neural network (CNN) to classify gyral and sulcal fMRI signals in the whole brain (the global model) and within functional brain networks (the local models). The frequency-specific difference between gyri and sulci is then inferred from the power spectral density (PSD) profiles of the learned filters in the CNN model. Our experimental results show that nfMRI shows higher gyral-sulcal PSD contrast effect sizes in the global model compared to rsfMRI. In the local models, the effect sizes are either increased or decreased depending on frequency bands and functional complexity of the FBNs. This study highlights the advantages of nfMRI in depicting the functional difference between gyri and sulci, and provides novel insights into unraveling the relationship between brain structure and function.

Novel Butenolide Derivatives as Dual-Chitinase Inhibitors to Arrest the Growth and Development of the Asian Corn Borer.

OfChtI and OfChi-h are considered potential targets for the control of Asian corn borer (Ostrinia furnacalis). In this work, the previously reported OfChtI inhibitor 5f was found to show certain inhibitory activity against OfChi-h (Ki = 5.81 µM). Two series of novel butenolide derivatives based on lead compound 5f were designed with the conjugate skeleton, contributing to the π-binding interaction to chitinase, and then synthesized. Compounds 4a-l and 7a-p displayed excellent inhibitory activities against OfChtI and OfChi-h, respectively, at a concentration of 10 µM. Compound 4h was found to be a good dual-Chitinase inhibitor, with Ki values of 1.82 and 2.00 µM against OfChtI and OfChi-h, respectively. The inhibitory mechanism studies by molecular docking suggested that π-π stacking interactions were crucial to the inhibitory activity of novel butenolide derivatives against two different chitinases. A preliminary bioassay indicated that 4h exhibited certain growth inhibition effects against O. furnacalis. Butenolide-like analogues should be further studied as promising novel dual-chitinase inhibitor candidates for the control of O. furnacalis.

Thermodynamic Driving Forces for the Self-Assembly of Diblock Polypeptoids.

Peptoid polymers with sequence-defined side chains are observed to self-assemble into a variety of structures spanning nanometer and micron scales. We explored a diblock copolypeptoid, poly(N-decylglycine)10-block-poly(N-2-(2-(2-methoxyethoxy)ethoxy)-ethylglycine)10 (abbreviated as Ndc10-Nte10), which forms crystalline nanofibers and nanosheets as evidenced by recent cryo-transmission electron microscopy, atomic force microscopy, X-ray diffraction, and calorimetry. Using all-atom molecular dynamics simulations, we examined the thermodynamic forces driving such self-assembly and how nanoscale morphology is tailored through modification of the N-terminus or via the addition of small molecules (urea). We have found that the hydrophobic Ndc domain alignment is key to the formation of molecular stacks whose growth is limited by electrostatic repulsion between protonated N-termini. These stacks are the building blocks that assemble via cooperative van der Waals attraction between the tips of extended decyl side chains to form nanofibers or nanosheets with a well-converged intermolecular interaction energy. Assemblies are significantly more stable in urea solution due to its strong attraction to the peptoid-solvent interface. Isolated peptoids exhibit curved all-cis backbones, which straighten within molecular stacks to maximize contact and registry between neighboring molecules. We hypothesize that competition between this attractive interaction and a strain cost for straightening the backbone is what leads to finite stack widths that define crystalline nanofibers of protonated Ndc10-Nte10. Growth is proposed to proceed through backbone unfurling via trans defects, which is more prevalent in aqueous solution than in THF, indicating a possible pathway to self-assembly under experimentally defined synthesis conditions (viz., THF evaporation).