Mask-Shift-Inference: A novel paradigm for domain generalization.

Domain Generalization (DG) focuses on the Out-Of-Distribution (OOD) generalization, which is able to learn a robust model that generalizes the knowledge acquired from the source domain to the unseen target domain. However, due to the existence of the domain shift, domain-invariant representation learning is challenging. Guided by fine-grained knowledge, we propose a novel paradigm Mask-Shift-Inference (MSI) for DG based on the architecture of Convolutional Neural Networks (CNN). Different from relying on a series of constraints and assumptions for model optimization, this paradigm novelly shifts the focus to feature channels in the latent space for domain-invariant representation learning. We put forward a two-branch working mode of a main module and multiple domain-specific sub-modules. The latter can only achieve good prediction performance in its own specific domain but poor predictions in other source domains, which provides the main module with the fine-grained knowledge guidance and contributes to the improvement of the cognitive ability of MSI. Firstly, during the forward propagation of the main module, the proposed MSI accurately discards unstable channels based on spurious classifications varying across domains, which have domain-specific prediction limitations and are not conducive to generalization. In this process, a progressive scheme is adopted to adaptively increase the masking ratio according to the training progress to further reduce the risk of overfitting. Subsequently, our paradigm enters the compatible shifting stage before the formal prediction. Based on maximizing semantic retention, we implement the domain style matching and shifting through the simple transformation through Fourier transform, which can explicitly and safely shift the target domain back to the source domain whose style is closest to it, requiring no additional model updates and reducing the domain gap. Eventually, the paradigm MSI enters the formal inference stage. The updated target domain is predicted in the main module trained in the previous stage with the benefit of familiar knowledge from the nearest source domain masking scheme. Our paradigm is logically progressive, which can intuitively exclude the confounding influence of domain-specific spurious information along with mitigating domain shifts and implicitly perform semantically invariant representation learning, achieving robust OOD generalization. Extensive experimental results on PACS, VLCS, Office-Home and DomainNet datasets verify the superiority and effectiveness of the proposed method.

Umpolung Strategy for the One-Pot Synthesis of Highly Steric Bispirooxindoles via the l-Amino Acid Ester-Promoted In Situ Reduction/Nucleophilic Addition/Cyclization Cascade Reaction.

On the basis of a novel umpolung strategy, an efficient l-amino acid ester-mediated in situ reduction of 2-(2-oxoindolin-3-ylidene)malononitrile and sequential nucleophilic addition/cyclization cascade reaction is reported. Various densely substituted cyclopentene bispirooxindoles and dihydrofuran bispirooxindoles with two quaternary spirocenters were constructed in high yields (≤93%) with excellent diastereoselectivities (>20:1 dr). The method has advantages of readily available starting materials, mild reaction conditions, a one-pot process, a metal-free biomimetic reducing agent, a wide substrate scope, and operational simplicity (single filtration without column chromatography).

Automatic renal carcinoma biopsy guidance using forward-viewing endoscopic optical coherence tomography and deep learning.

Percutaneous renal biopsy is commonly used for kidney cancer diagnosis. However, the biopsy procedure remains challenging in sampling accuracy. Here we introduce a forward-viewing optical coherence tomography probe for differentiating tumor and normal tissues, aiming at precise biopsy guidance. Totally, ten human kidney samples, nine of which had malignant renal carcinoma and one had benign oncocytoma, were used for system evaluation. Based on their distinct imaging features, carcinoma could be efficiently distinguished from normal renal tissues. Additionally, oncocytoma could be differentiated from carcinoma. We developed convolutional neural networks for tissue recognition. Compared to the conventional attenuation coefficient method, convolutional neural network models provided more accurate carcinoma predictions. These models reached a tissue recognition accuracy of 99.1% on a hold-out set of four kidney samples. Furthermore, they could efficiently distinguish oncocytoma from carcinoma. In conclusion, our convolutional neural network-aided endoscopic imaging platform could enhance carcinoma diagnosis during percutaneous renal biopsy procedures.

Efficient removal of Cr(VI) from contaminated kaolin and anolyte by electrokinetic remediation with foamed iron anode electrode and acetic acid electrolyte.

Combined electrokinetic remediation employing reducing agents represents an extensively utilized approach for the remediation of hexavalent chromium (Cr(VI))-contaminated soil. In this investigation, electrokinetic remediation of artificially contaminated kaolin was conducted utilizing a separate circulation system for the anolyte, with a 0.5M solution of acetic acid (HAc) as the electrolyte and foamed iron serving as the anode. The experimental outcomes demonstrated that employing HAc as the electrolyte enhances the electromigration of Cr(VI) and establishes an acidic milieu conducive to the reduction of Cr(VI) by foamed iron, thereby facilitating the rapid reduction of Cr(VI) accumulated in the anolyte through electrokinetic remediation. In the self-prepared contaminated kaolin, the initial concentration of Cr(VI) was 820.26 mg/L. Following the remediation process under optimal experimental conditions, the concentration was significantly reduced to 11.6 mg/L, achieving a removal efficiency of Cr(VI) in the soil of 98.59%. In the optimal experimental setup, the Cr(VI) concentration in the anolyte was reduced to 0.05 mg/L, which is below the EPA's Safe Drinking Water Act standard for Cr(VI) content of 0.1 mg/L. The removal mechanism of Cr(VI) from the electrolyte primarily involves reduction, precipitation, and co-precipitation, with the foamed iron playing a predominant role. HAc and foamed iron exhibit a synergistic effect. The findings of this study substantiate that the integration of foamed iron with HAc is efficacious for the electrokinetic remediation of soil contaminated with Cr(VI).

Multiple pathways of vanadate reduction and denitrification mediated by denitrifying bacterium Acidovorax sp. strain BoFeN1.

Contamination of aquifers by a combination of vanadate [V(V)] and nitrate (NO3-) is widespread nowadays. Although bioremediation of V(V)- and nitrate-contaminated environments is possible, only a limited number of functional species have been identified to date. The present study demonstrates the effectiveness of V(V) reduction and denitrification by a denitrifying bacterium Acidovorax sp. strain BoFeN1. The V(V) removal efficiency was 76.5 ± 5.41 % during 120 h incubation, with complete removal of NO3- within 48 h. Inhibitor experiments confirmed the involvement of electron transport substances and denitrifying enzymes in the bioreduction of V(V) and NO3-. Cyt c and riboflavin were important for extracellular V(V) reduction, with quinone and EPS more significant for NO3- removal. Intracellular reductive compounds including glutathione and NADH directly reduce V(V) and NO3-. Reverse transcription quantitative PCR confirmed the important roles of nirK and napA genes in regulating V(V) reduction and denitrification. Bioaugmentation by strain BoFeN1 increased V(V) and NO3- removal efficiency by 55.3 % ± 2.78 % and 42.1 % ± 1.04 % for samples from a contaminated aquifer. This study proposes new microbial resources for the bioremediation of V(V) and NO3-contaminated aquifers, and contributes to our understanding of coupled vanadium, nitrogen, and carbon biogeochemical processes.

Aging atlas reveals cell-type-specific effects of pro-longevity strategies.

Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms.

Optical coherence tomography for multicellular tumor spheroid category recognition and drug screening classification via multi-spatial-superficial-parameter and machine learning.

Optical coherence tomography (OCT) is an ideal imaging technique for noninvasive and longitudinal monitoring of multicellular tumor spheroids (MCTS). However, the internal structure features within MCTS from OCT images are still not fully utilized. In this study, we developed cross-statistical, cross-screening, and composite-hyperparameter feature processing methods in conjunction with 12 machine learning models to assess changes within the MCTS internal structure. Our results indicated that the effective features combined with supervised learning models successfully classify OVCAR-8 MCTS culturing with 5,000 and 50,000 cell numbers, MCTS with pancreatic tumor cells (Panc02-H7) culturing with the ratio of 0%, 33%, 50%, and 67% of fibroblasts, and OVCAR-4 MCTS treated by 2-methoxyestradiol, AZD1208, and R-ketorolac with concentrations of 1, 10, and 25 µM. This approach holds promise for obtaining multi-dimensional physiological and functional evaluations for using OCT and MCTS in anticancer studies.

Pharmacological and mechanistic aspects of quercetin in osteoporosis.

Osteoporosis (OP) is a bone disease associated with increasing age. Currently, the most common medications used to treat OP are anabolic agents, anti-resorptive agents, and medications with other mechanisms of action. However, many of these medications have unfavorable adverse effects or are not intended for long-term use, potentially exerting a severe negative impact on a patient's life and career and placing a heavy burden on families and society. There is an urgent need to find new drugs that can replace these and have fewer adverse effects. Quercetin (Que) is a common flavonol in nature. Numerous studies have examined the therapeutic applications of Que. However, a comprehensive review of the anti-osteoporotic effects of Que has not yet been conducted. This review aimed to describe the recent studies on the anti-osteoporotic effects of Que, including its biological, pharmacological, pharmacokinetic, and toxicological properties. The outcomes demonstrated that Que could enhance OP by increasing osteoblast differentiation and activity and reducing osteoclast differentiation and activity via the pathways of Wnt/ß-catenin, BMP/SMAD/RUNX2, OPG/RANKL/RANK, ERK/JNK, oxidative stress, apoptosis, and transcription factors. Thus, Que is a promising novel drug for the treatment of OP.

Dimension-based quantification of aging-associated cerebral microvasculature determined by optical coherence tomography and two-photon microscopy.

Cerebral microvascular health is a key biomarker for the study of natural aging and associated neurological diseases. Our aim is to quantify aging-associated change of microvasculature at diverse dimensions in mice brain. We used optical coherence tomography (OCT) and two-photon microscopy (TPM) to obtain nonaged and aged C57BL/6J mice cerebral microvascular images in vivo. Our results indicated that artery & vein, arteriole & venule, and capillary from nonaged and aged mice showed significant differences in density, diameter, complexity, perimeter, and tortuosity. OCT angiography and TPM provided the comprehensive quantification for arteriole and venule via compensating the limitation of each modality alone. We further demonstrated that arteriole and venule at specific dimensions exhibited negative correlations in most quantification analyses between nonaged and aged mice, which indicated that TPM and OCT were able to offer complementary vascular information to study the change of cerebral blood vessels in aging.

Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity.

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMP-activated protein kinase and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin-positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk, and organism longevity.

Enhancing epidural needle guidance using a polarization-sensitive optical coherence tomography probe with convolutional neural networks.

Epidural anesthesia helps manage pain during different surgeries. Nonetheless, the precise placement of the epidural needle remains a challenge. In this study, we developed a probe based on polarization-sensitive optical coherence tomography (PS-OCT) to enhance the epidural anesthesia needle placement. The probe was tested on six porcine spinal samples. The multimodal imaging guidance used the OCT intensity mode and three distinct PS-OCT modes: (1) phase retardation, (2) optic axis, and (3) degree of polarization uniformity (DOPU). Each mode enabled the classification of different epidural tissues through distinct imaging characteristics. To further streamline the tissue recognition procedure, convolutional neural network (CNN) were used to autonomously identify the tissue types within the probe's field of view. ResNet50 models were developed for all four imaging modes. DOPU imaging was found to provide the highest cross-testing accuracy of 91.53%. These results showed the improved precision by PS-OCT in guiding epidural anesthesia needle placement.

Automatic renal carcinoma biopsy guidance using forward-viewing endoscopic optical coherence tomography and deep learning.

Percutaneous renal biopsy (PRB) is commonly used for kidney cancer diagnosis. However, current PRB remains challenging in sampling accuracy. This study introduces a forward-viewing optical coherence tomography (OCT) probe for differentiating tumor and normal tissues, aiming at precise PRB guidance. Five human kidneys and renal carcinoma samples were used to evaluate the performance of our probe. Based on their distinct OCT imaging features, tumor and normal renal tissues can be accurately distinguished. We examined the attenuation coefficient for tissue classification and achieved 98.19% tumor recognition accuracy, but underperformed for distinguishing normal tissues. We further developed convolutional neural networks (CNN) and evaluated two CNN architectures: ResNet50 and InceptionV3, yielding 99.51% and 99.48% accuracies for tumor recognition, and over 98.90% for normal tissues recognition. In conclusion, combining OCT and CNN significantly enhanced the PRB guidance, offering a promising guidance technology for improved kidney cancer diagnosis.

Clinical Study on the Treatment of Non-isotropic Cervical Spondylosis by Neck Pain Granules Combined with Tuina.

BACKGROUND: Cervical spondylotic radiculopathy is a common form of cervical spondylosis caused by degeneration of the cervical spine. Currently, non-surgical treatment is the preferred treatment method, and Chinese medicine is widely used. OBJECTIVE: To investigate the effect of radiculopathy spondylosis by tuina spinning and lifting technique. EXPERIMENTAL DESIGN: We conducted a 12-week, open-label, analyst-blinded, randomized clinical trial ( 2 weeks of intervention plus 10 weeks of observational follow-up ). A total of 25 patients with radiculopathy were collected, and data was analyzed during the treatment and recovery period. INTERVENTIONS: Neck pain granules group: a package of oral neck pain granules after meals, three times a day, treatment for 2 weeks; neck pain granules combined with massage lifting technique, treatment group: use, massage lifting technique treatment, once every two days, normal take neck pain granules, treatment for 2 weeks. All cases were followed up for 2.5 months. Main monitoring indicators: Visual Analog Scale, Neck Dysfunction Index score, and Tanaka jiu ( Tanaka Yasuhisa Cervical Spondylosis Symptom Scale ) were recorded on time, and statistical statistics were made. RESULT: The scores of VAS and NDI were significantly more effective in the neck pain granules combined with the tuina group than in the neck pain granules group, while the Tanaka Yasuhisa Cervical Spondylosis Symptom Scale was not significantly different between the two groups. CONCLUSION: The treatment effect of neck pain granules combined with tuina was significantly better than that of traditional Chinese medicine alone.

Optical Coherence Tomography of Tumor Spheroids Identifies Candidates for Drug Repurposing in Ovarian Cancer.

OBJECTIVE: Multicellular tumor spheroids (MCTs) are indispensable models for evaluating drug efficacy for precision cancer therapeutic strategies as well as for repurposing FDA-approved drugs for ovarian cancer. However, current imaging techniques cannot provide effective monitoring of pathological responses due to shallow penetration and experimentally operative destruction. We plan to utilize a noninvasive optical imaging tool to achieve in vivo longitudinal monitoring of the growth of MCTs and therapeutic responses to repurpose three FDA-approved drugs for ovarian cancer therapy. METHODS: A swept-source optical coherence tomography (SS-OCT) system was used to monitor the volume growth of MCTs over 11 days. Three inhibitors of 2-Methoxyestradiol (2-ME), AZD1208, and R-Ketorolac (R-keto) with concentrations of 1, 10, and 25 µM were employed to treat ovarian MCTs on day 5. Three-dimensional (3D), intrinsic optical attenuation contrast, and degree of uniformity were applied to analyze the therapeutic effect of these inhibitors on ovarian MCTs. RESULTS: We found that 2-ME, AZD1208, and R-keto with concentration of 10 and 25 µM significantly inhibited the volume growth of ovarian MCTs. There was no effect to necrotic tissues from all concentrations of 2-ME, AZD1208, and R-keto inhibitors from our OCT results. 2-ME and AZD1208 inhibited the growth of high uniformity tissues within MCTs and higher concentrations provided more significant inhibitory effects. CONCLUSION: Our results indicated that OCT was capable and reliable to monitor the therapeutic effect of inhibitors to ovarian MCTs and it can be used for the rapid characterization of novel therapeutics for ovarian cancers in the future.

Aging Atlas Reveals Cell-Type-Specific Regulation of Pro-longevity Strategies.

Organism aging occurs at the multicellular level; however, how pro-longevity mechanisms slow down aging in different cell types remains unclear. We generated single-cell transcriptomic atlases across the lifespan of Caenorhabditis elegans under different pro-longevity conditions (http://mengwanglab.org/atlas). We found cell-specific, age-related changes across somatic and germ cell types and developed transcriptomic aging clocks for different tissues. These clocks enabled us to determine tissue-specific aging-slowing effects of different pro-longevity mechanisms, and identify major cell types sensitive to these regulations. Additionally, we provided a systemic view of alternative polyadenylation events in different cell types, as well as their cell-type-specific changes during aging and under different pro-longevity conditions. Together, this study provides molecular insights into how aging occurs in different cell types and how they respond to pro-longevity strategies.

Serum neutrophil gelatinase-associated lipocalin as a potential biomarker for cognitive decline in spinal cord injury.

Objective: Neutrophil gelatinase-associated lipoprotein (NGAL), a protein encoded by the lipocalcin-2 (LCN2) gene, has been reported to be involved in multiple processes of innate immunity, but its relationship with spinal cord injury (SCI) remains unclear. This study set out to determine whether NGAL played a role in the development of cognitive impairment following SCI. Methods: At the Neck-Shoulder and Lumbocrural Pain Hospital, a total of 100 SCI patients and 72 controls were enrolled in the study through recruitment. Through questionnaires, baseline data on the participants' age, gender, education level, lifestyle choices (drinking and smoking) and underlying illnesses (hypertension, diabetes, coronary heart disease, and hyperlipidemia) were gathered. The individuals' cognitive performance was evaluated using the Montreal Cognitive Scale (MoCA), and their serum NGAL levels were discovered using ELISA. Results: The investigation included 72 controls and 100 SCI patients. The baseline data did not differ substantially between the two groups, however the SCI group's serum NGAL level was higher than the control group's (p < 0.05), and this elevated level was adversely connected with the MoCA score (p < 0.05). According to the results of the ROC analysis, NGAL had a sensitivity of 58.24% and a specificity of 86.72% for predicting cognitive impairment following SCI. Conclusions: The changes in serum NGAL level could serve as a biomarker for cognitive impairment in SCI patients, and this holds true even after taking in account several confounding variables.

A BMP-2-triggered in vivo osteo-organoid for cell therapy.

Cell therapies and regenerative medicine interventions require an adequate source of therapeutic cells. Here, we demonstrate that constructing in vivo osteo-organoids by implanting bone morphogenetic protein-2-loaded scaffolds into the internal muscle pocket near the femur of mice supports the growth and subsequent harvest of therapeutically useful cells including hematopoietic stem/progenitor cells (HSPCs), mesenchymal stem cells (MSCs), lymphocytes, and myeloid cells. Profiling of the in vivo osteo-organoid maturation process delineated three stages-fibroproliferation, osteochondral differentiation, and marrow generation-each of which entailed obvious changes in the organoid structure and cell type distribution. The MSCs harvested from the osteochondral differentiation stage mitigated carbon tetrachloride (CCl4)-induced chronic liver fibrosis in mice, while HSPCs and immune cells harvested during the marrow generation stage rapidly and effectively reconstituted the impaired peripheral and solid immune organs of irradiated mice. These findings demonstrate the therapeutic potentials of in vivo osteo-organoid-derived cells in cell therapies.

Examining the Nonlinear and Synergistic Effects of Multidimensional Elements on Commuting Carbon Emissions: A Case Study in Wuhan, China.

Understanding the specific effects of multidimensional elements of a built environment, transportation management policies, and the socio-demographics of travelers associated with commuting carbon emissions is significant for planners in promoting low-carbon and healthy urban development through transportation and land use and urban management policies. Most of the existing studies focus on the complex mechanisms affecting commuting behavior, but the relevant elements and specific mechanisms affecting commuting carbon emissions have not received sufficient attention. This study uses a random forest approach to analyze residential travel data from Wuhan, China. The results show that built environment and transportation demand management policies are critical to commuting carbon emissions, and that there is a non-linear association between multidimensional factors and commuting carbon emissions in Chinese cities. In addition, the study examines the synergistic effects of built environment and transportation management policies on commuting carbon emissions among different built environment elements. The results of the study provide valuable insights for planners in formulating low-carbon city and transportation development policies.

Laser-Induced Combinatorial Chemotherapeutic, Chemodynamic, and Photothermal Therapy for Hepatocellular Carcinoma Based on Oxaliplatin-Loaded Metal-Organic Frameworks.

The activation of nanoparticles (NPs) in the tumor microenvironment exerts synergistic therapeutic effects with chemotherapy against multiple cancers. In this study, an NP system prepared using biocompatible MIL-100 NPs was studied as an effective vehicle to deliver oxaliplatin for hepatocellular carcinoma treatment. The NPs were coated with polydopamine (PDA) and NH2-PEGTK-COOH and then loaded with oxaliplatin to create the multi-functional NP Oxa@MIL-PDA-PEGTK. Oxa@MIL-PDA-PEGTK is activated in the tumor microenvironment, causing the generation of cytotoxic reactive oxygen species (ROS) via the Fenton reaction and the release of the loaded oxaliplatin. In addition, under near-infrared (NIR) irradiation, Oxa@MIL-PDA-PEGTK can generate hyperthermia at tumor sites. Moreover, owing to the light-induced activation of the Oxa@MIL-PDA-PEGTK NPs, higher drug delivery efficiency, more precise targeted activation, and reduced off-target toxicity were observed in in vitro and in vivo experiments. Taken together, owing to its improved drug delivery efficiency and multi-functional activities, including the ability for targeted chemotherapy coupled with photothermal and chemodynamic therapy, Oxa@MIL-PDA-PEGTK may serve as a new approach for treating hepatocellular carcinoma.

Recapitulation of growth factor-enriched microenvironment via BMP receptor activating hydrogel.

Exposure to a growth factor abundant milieu has remarkable regenerative and rejuvenating effects on organ diseases, tissue damage, and regeneration, including skeletal system defects and bone regeneration. Although the introduction of candidate growth factors into relevant fields has been reported, their regenerative effects remain unsatisfactory, mainly because of the experimental challenges with limited types of growth factors, elusive dosage adjustment, and asynchronous stem cell activation with cytokine secretion. Here, an innovative hydrogel recapitulating a growth factor-enriched microenvironment (GEM) for regenerative advantage, is reported. This sulfated hydrogel includes bone morphogenetic protein-2 (BMP-2), an essential growth factor in osteogenesis, to direct mesenchymal stem cell (MSC) differentiation, stimulate cell proliferation, and improve bone formation. The semi-synthetic hydrogel, sulfonated gelatin (S-Gelatin), can amplify BMP-2 signaling in mouse MSCs by enhancing the binding between BMP-2 and BMP-2 type II receptors (BMPR2), which are located on MSC nuclei and activated by the hydrogel. Importantly, the dramatically improved cytokine secretion of MSCs throughout regeneration confirms the growth factor-acquiring potential of S-Gelatin/rhBMP-2 hydrogel, leading to the vascularization enhancement. These findings provide a new strategy to achieve an in situ GEM and accelerated bone regeneration by amplifying the regenerative capacity of rhBMP-2 and capturing endogenous growth factors.