Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.

JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

Multiple pulp stones emerge across all teeth during mixed dentition: A case report.

BACKGROUND: This paper reports a rare presentation of multiple pulp stones (PSs) emerging in all teeth during mixed dentition. It offers valuable insights into the clinical diagnosis, treatment, and prognosis of multiple PSs, shedding light on their occurrence during the mixed dentition period. CASE SUMMARY: A 10-year-old girl presented with repeated pain in the mandibular right posterior teeth. Intraoral examination revealed carious lesions, abnormal tooth shapes, and anomalies in tooth number. Radiographic examinations showed multiple PSs with diverse shapes, sizes, and quantities in all teeth, alongside anomalies in tooth shape and number. Root canal therapy was initiated, but the patient initially lacked timely follow-up. Upon return for treatment completion, an extracted tooth revealed irregular calculus within the pulp cavity. CONCLUSION: This case underscores the importance of considering multiple PSs in mixed dentition, necessitating comprehensive evaluation and management strategies.

Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus.

Objective: We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. Method: We first induced lupus-like disease in T cell specific Rictor , a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti- Rictor antisense oligonucleotide ( Rictor -ASO) in a mouse model of lupus: MRL/ lpr mice. Finally, we examined the beneficial effects of RICTOR -ASO on SLE patients' PBMCs using an in vitro T-B cell coculture assay. Results: T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4 + T cells accompanied by restored CD4 + T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor -ASO treatment improves renal function and pathology in MRL/ lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR- ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05). Conclusion: Targeting mTORC2 could be a promising therapeutic for SLE.

[Determination of the derivatization reactivity between α/ß-dicarbonyl compounds and standard citrullinated peptides based on matrix-assisted laser desorption ionization-time-of-flight mass spectrometry].

Protein citrullination is an irreversible post-translational modification process regulated by peptidylarginine deiminases (PADs) in the presence of Ca2+. This process is closely related to the occurrence and development of autoimmune diseases, cancers, neurological disorders, cardiovascular and cerebrovascular diseases, and other major diseases. The analysis of protein citrullination by biomass spectrometry confronts great challenges owing to its low abundance, lack of affinity tags, small mass-to-charge ratio change, and susceptibility to isotopic and deamidation interferences. The methods commonly used to study the protein citrullination mainly involve the chemical derivatization of the urea group of the guanine side chain of the peptide to increase the mass-to-charge ratio difference of the citrullinated peptide. Affinity-enriched labels are then introduced to effectively improve the sensitivity and accuracy of protein citrullination by mass spectrometry. 2,3-Butanedione or phenylglyoxal compounds are often used as derivatization reagents to increase the mass-to-charge ratio difference of the citrullinated peptide, and the resulting derivatives have been observed to contain α-dicarbonyl structures. To date, however, no relevant studies on the reactivity of dicarbonyl compounds with citrullinated peptides have been reported. In this study, we determined whether six α-dicarbonyl and two ß-dicarbonyl compounds undergo derivatization reactions with standard citrullinated peptides using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Among the α-dicarbonyl compounds, 2,3-butanedione and glyoxal reacted efficiently with several standard citrullinated peptides, but yielded a series of by-products. Phenylglyoxal, methylglyoxal, 1,2-cyclohexanedione, and 1,10-phenanthroline-5,6-dione also derivated efficiently with standard citrullinated peptides, generating a single derivative. Thus, a new derivatization method that could yield a single derivative was identified. Among the ß-dicarbonyl compounds, 1,3-cyclohexanedione and 2,4-pentanedione successfully reacted with the standard citrullinated peptides, and generated a single derivative. However, their reaction efficiency was very low, indicating that the ß-dicarbonyl compounds are unsuitable for the chemical derivatization of citrullinated peptides. The above results indicate that the α-dicarbonyl structure is necessary for realizing the efficient and specific chemical derivatization of citrullinated peptides. Moreover, the side chains of the α-dicarbonyl structure determine the structure of the derivatives, derivatization efficiency, and generation (or otherwise) of by-products. Therefore, the specific enrichment and precise identification of citrullinated peptides can be achieved by synthesizing α-dicarbonyl structured compounds containing affinity tags. The proposed method enables the identification of citrullinated proteins and their modified sites by MS, thereby providing a better understanding of the distribution of citrullinated proteins in different tissues. The findings will be beneficial for studies on the mechanism of action of citrullinated proteins in a variety of diseases.

Screening and identification of peptidyl arginine deiminase 4 inhibitors from herbal plants extracts and purified natural products by a trypsin assisted sensitive immunoassay based on streptavidin magnetic beads.

Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC50 value lower than 5 µg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC50 value lower than 4 µM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4.

Terahertz flexible multiplexing chip enabled by synthetic topological phase transitions.

Flexible multiplexing chips that permit reconfigurable multidimensional channel utilization are indispensable for revolutionary 6G terahertz communications, but the insufficient manipulation capability of terahertz waves prevents their practical implementation. Herein, we propose the first experimental demonstration of a flexible multiplexing chip for terahertz communication by revealing the unique mechanism of topological phase (TP) transition and perseveration in a heterogeneously coupled bilayer valley Hall topological photonic system. The synthetic and individual TPs operated in the coupled and decoupled states enable controllable on-chip modular TP transitions and subchannel switching. Two time-frequency interleaved subchannels support 10- and 12-Gbit/s QAM-16 high-speed data streams along corresponding paths over carriers of 120 and 130 GHz with 2.5- and 3-GHz bandwidths, respectively. This work unlocks interlayer heterogeneous TPs for inspiring ingenious on-chip terahertz-wave regulation, allowing functionality-reconfigurable, compactly integrated and CMOS-compatible chips.

A Peculiar Tau Accumulation Pattern Identified Via 18F-Florzolotau PET Imaging in a Patient With Frontotemporal Dementia Caused by a Mutation in the MAPT Gene.

ABSTRACT: We reported imaging findings with a peculiar tau accumulation pattern in a 56 year-old woman with frontotemporal dementia caused by Q351R mutation in the microtubule-associated protein tau (MAPT) gene. She had a 10-year history of gradually worsening memory loss. 18F-FDG PET demonstrated hypometabolism in medial temporal lobes, but 18F-florbetapir PET manifested no abnormal amyloid beta deposition, which ruled out Alzheimer disease. 18F-florzolotau PET showed tau proteins accumulated in medial temporal lobes, basal ganglia brainstem, and cerebellum. The pattern is different from other known MAPT gene mutation. Multitracer imaging can help differentiate between Alzheimer disease and frontotemporal dementia caused by MAPT mutation.

Immobilized PAD4 enzyme on magnetic nanoparticles for screening natural inhibitors from traditional Chinese medicines.

Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has emerged as potential and promising therapeutic target. However, no PAD4 inhibitor is ready for clinical use. Immobilized enzyme screening technology has gained increasing attention due to its low cost, reusability, easy separation from the reaction mixture, and resistance to changes in environmental conditions. In this study, PAD4 was immobilized on the magnetic nanoparticles (MNP) to prolong its activity stability, and a simple and rapid screening strategy of traditional Chinese medicine inhibitors based on immobilized PAD4 was established. The PAD4 enzyme was immobilized on magnetic nanoparticles (MNP) via Schiff base reaction using glutaraldehyde (GA) as crosslinking agent. Compared with free PAD4, the resulting MNP@GA@PAD4 exhibited an enhanced tolerance to temperature and storage stability, and its reusability was greatly improved with 66 % of initial enzyme activity after being recycled 10 times. The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine. The semi-maximum inhibitory concentrations (IC50) of GSK484 and BB-Cl-amidine for MNP@GA@PAD4 were 1.00 and 0.97 µM, respectively, for free PAD4 were 0.64 and 0.85 µM, respectively. Finally, the MNP@GA@PAD4 was employed to rapid screen of natural PAD4 inhibitors from forty traditional Chinese medicines (TCMs). Under the same conditions, the controlled experiment was conducted with free PAD4. The screening results of TCMs inhibitors on MNP@GA@PAD4 and free PAD4 were similar, the alcohol extracts of Cinnamomi Cortex and Caryophylli Flos had significant inhibitory effects on PAD4 enzyme activity. The IC50 values of Cinnamomi Cortex extract for MNP@GA@PAD4 and free PAD4 were determined as 27 and 48 µg/mL, respectively. The IC50 values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 µg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs.

PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses.

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8+ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα-deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8+ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8+ T-cell homeostasis and effector functions.

Styxl2 regulates de novo sarcomere assembly by binding to non-muscle myosin IIs and promoting their degradation.

Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.

Diagnosing Tabes Dorsalis in HIV-Negative Patients: Clinical Features, Neuroimaging, and Laboratory Insights in the Modern Antibiotic Era.

Background: Tabes dorsalis is a late manifestation of neurosyphilis, characterized by progressive ataxia, lightning pains, loss of proprioception, and urinary incontinence. The absence of a definitive diagnostic standard and the non-specific clinical manifestations have led to a significant rate of misdiagnoses. Methods: Hospitalized patients with tabes dorsalis at Peking Union Medical College Hospital between January 2010 and December 2023 were reviewed. Results: A total of 13 patients were included, with 10 males and 3 females. The median age was 50 years (range, 34-64). The most frequent initial symptoms were limb numbness (30.8%) and lightning pains (30.8%). Eleven patients (84.6%) received misdiagnoses prior to the final diagnosis. The most frequently observed physical sign was positive Romberg's sign (84.6%). Notably, Argyll Robertson pupil was presented in 7 subjects (53.8%). Serological tests revealed positive rapid plasma regain (RPR) and Treponema pallidum particle agglutination (TPPA) for all patients. All CSF samples were TPPA-reactive. Intramedullary hyperintensity on T2-weighted imaging of spinal MRI was found in 5 patients (38.5%). All patients received anti-syphilitic treatment, with effective treatment recorded in five cases. Conclusion: This study underscores the importance of neurological symptoms and signs in diagnosing tabes dorsalis. Individuals with progressive ataxia and positive Romberg's sign should be closely monitored for potential neurosyphilis. Integrating clinical features, laboratory tests, and neuroimaging could reduce misdiagnosis and expedite the initiation of anti-syphilitic therapy.

Immunodeviation towards T cell-mediated immune response in the testes of LPS-induced mouse epididymo-orchitis.

The testicular consequences of acute epididymo-orchitis remain largely unelucidated in long-term damage, which might be a neglected factor for male infertility. In this study, the differential phenotype of testicular immune cell subpopulations in lipopolysaccharide (LPS)-induced mouse epididymo-orchitis were analyzed by flow cytometry on day 1, day 7, and day 28. The number of macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs) steadily decreased in the testes with inoculation. Total F4/80-CD11c+ dendritic cells (DCs) maintained a relatively stable level, whereas conventional type 1 dendritic cells (cDC1) increased gradually from day 1 to day 28. There was a lower number of CD4+ and CD8+ T cells at day 1 and day 7, and they had similar results with a ceiling level at day 28. The testes displayed a higher level of CD3+ T cells but a lower frequency of macrophages, cDC2, and neutrophils at 28 days post-inoculation compared with the epididymis. In summary, our data indicates acute epididymo-orchitis could lead to long-term damage in the testes, which is characterized by CD3+ T cell (including CD4+ and CD8+ T cells)-mediated immune responses.

Facile Access to Branched Multispecific Proteins.

Approaches that leverage orthogonal chemical reactions to generate protein-protein conjugates have expanded access to bespoke chimeras. Although the literature is replete with examples of the semisynthesis of bispecific proteins, few methods exist for the semisynthesis of protein conjugates of higher complexity (i.e., greater than two-protein fusions). The recent emergence of trispecific cell engagers for immune cell redirection therapies necessitates the development of chemical methods for the construction of trispecific proteins that would otherwise be inaccessible via natural protein synthesis. Here, we demonstrate that 3-bromo-5-methylene pyrrolone (3Br-5MP) can be used to effect the facile chemical synthesis of trispecific peptides and proteins with exquisite control over the addition of each monomer. The multimeric complexes maintain epitope functionality both in human cells and upon immobilization. We anticipate that facile access to trispecific proteins using this 3Br-5MP will have broad utility in basic science research and will quicken the pace of research to establish novel, multimeric immune cell redirection therapies.

Analyzing variation of water inflow to inland lakes under climate change: Integrating deep learning and time series data mining.

The alarming depletion of global inland lakes in recent decades makes it essential to predict water inflow from rivers to lakes (WIRL) trend and unveil the dominant influencing driver, particularly in the context of climate change. The raw time series data contains multiple components (i.e., long-term trend, seasonal periodicity, and random noise), which makes it challenging for traditional machine/deep learning techniques to effectively capture long-term trend information. In this study, a novel FactorConvSTLnet (FCS) method is developed through integrating STL decomposition, convolutional neural networks (CNN), and factorial analysis into a general framework. FCS is more robust in long-term WIRL trend prediction through separating trend information as a modeling predictor, as well as unveiling predominant drivers. FCS is applied to typical inland lakes (the Aral Sea and the Lake Balkhash) in Central Asia, and results indicate that FCS (Nash-Sutcliffe efficiency = 0.88, root mean squared error = 67m³/s, mean relative error = 10%) outperforms the traditional CNN. Some main findings are: (i) during 1960-1990, reservoir water storage (WSR) was the dominant driver for the two lakes, respectively contributing to 71% and 49%; during 1991-2014 and 2015-2099, evaporation (EVAP) would be the dominant driver, with the contribution of 30% and 47%; (ii) climate change would shift the dominant driver from human activities to natural factors, where EVAP and surface snow amount (SNW) have an increasing influence on WIRL; (iii) compared to SSP1-2.6, the SNW contribution would decrease by 26% under SSP5-8.5, while the EVAP contribution would increase by 9%. The findings reveal the main drivers of shrinkage of the inland lakes and provide the scientific basis for promoting regional ecological sustainability.

Screening of peptidyl arginine deiminase 4 inhibitors in traditional herbal medicines.

Peptidyl arginine deiminase 4 (PAD4) is a promising target for the treatment of metabolic diseases associated with autoimmune and central nervous system disease. By now there are limited numbers of PAD4 inhibitors, and no one is ready for clinical use. This study aims to find efficient and specific PAD4 inhibitors from traditional herbal medicines and to investigate their inhibitory mechanisms. The inhibitory effects of forty-eight extracts from sixteen traditional herbal medicines which are widely used in traditional herbal medicines were investigated. Salvia miltiorrhiza was found to have the most potent PAD4 inhibitory activity. After that, a practical bioactivity-guided fractionation coupling with a chemical profiling strategy was used to identify the fractions from Salvia miltiorrhiza with strong PAD4 inhibition activity, and the major constituents in these bioactive fractions were characterized by LC-MS/MS. Seven compounds were found to have inhibition on PAD4 with IC50 values ranging from 33.52 µM to 667 µM, in which salvianolic acid A showed the most potent inhibitory activity, with an IC50 value of 33.52 µM. Inhibition kinetic analyses indicated that salvianolic acid A effectively inhibited PAD4 in a mixed inhibitory manner, and computer simulation analyses demonstrated that salvianolic acid A binds to PAD4 mainly using hydrogen bonding. Overall, our results suggest that salvianolic acid A from Salvia miltiorrhiza is a potent inhibitor of PAD4, and that salvianolic acid A can be used as a promising lead compound for the development of more potent PAD4 inhibitors.

Revolutionizing breast cancer Ki-67 diagnosis: ultrasound radiomics and fully connected neural networks (FCNN) combination method.

PURPOSE: This study aims to assess the diagnostic value of ultrasound habitat sub-region radiomics feature parameters using a fully connected neural networks (FCNN) combination method L2,1-norm in relation to breast cancer Ki-67 status. METHODS: Ultrasound images from 528 cases of female breast cancer at the Affiliated Hospital of Xiangnan University and 232 cases of female breast cancer at the Affiliated Rehabilitation Hospital of Xiangnan University were selected for this study. We utilized deep learning methods to automatically outline the gross tumor volume and perform habitat clustering. Subsequently, habitat sub-regions were extracted to identify radiomics features and underwent feature engineering using the L1,2-norm. A prediction model for the Ki-67 status of breast cancer patients was then developed using a FCNN. The model's performance was evaluated using accuracy, area under the curve (AUC), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), Recall, and F1. In addition, calibration curves and clinical decision curves were plotted for the test set to visually assess the predictive accuracy and clinical benefit of the models. RESULT: Based on the feature engineering using the L1,2-norm, a total of 9 core features were identified. The predictive model, constructed by the FCNN model based on these 9 features, achieved the following scores: ACC 0.856, AUC 0.915, Spe 0.843, PPV 0.920, NPV 0.747, Recall 0.974, and F1 0.890. Furthermore, calibration curves and clinical decision curves of the validation set demonstrated a high level of confidence in the model's performance and its clinical benefit. CONCLUSION: Habitat clustering of ultrasound images of breast cancer is effectively supported by the combined implementation of the L1,2-norm and FCNN algorithms, allowing for the accurate classification of the Ki-67 status in breast cancer patients.

Automatic breast ultrasound (ABUS) tumor segmentation based on global and local feature fusion.

Accurate segmentation of tumor regions in automated breast ultrasound (ABUS) images is of paramount importance in computer-aided diagnosis system. However, the inherent diversity of tumors and the imaging interference pose great challenges to ABUS tumor segmentation. In this paper, we propose a global and local feature interaction model combined with graph fusion (GLGM), for 3D ABUS tumor segmentation. In GLGM, we construct a dual branch encoder-decoder, where both local and global features can be extracted. Besides, a global and local feature fusion module is designed, which employs the deepest semantic interaction to facilitate information exchange between local and global features. Additionally, to improve the segmentation performance for small tumors, a graph convolution-based shallow feature fusion module is designed. It exploits the shallow feature to enhance the feature expression of small tumors in both local and global domains. The proposed method is evaluated on a private ABUS dataset and a public ABUS dataset. For the private ABUS dataset, the small tumors (volume smaller than 1 cm3) account for over 50% of the entire dataset. Experimental results show that the proposed GLGM model outperforms several state-of-the-art segmentation models in 3D ABUS tumor segmentation, particularly in segmenting small tumors.

A novel MAPT variant (E342K) as a cause of familial progressive supranuclear palsy.

Background: MAPT variants are a known cause of frontotemporal dementia and Parkinsonian syndrome, of which progressive supranuclear palsy syndrome (PSP) is a rare manifestation. Objective: To report a novel MAPT variant in a PSP pedigree with autosomal dominant inheritance pattern, and to produce a literature review of PSP patients with MAPT variants. Methods: A comprehensive clinical, genetic, and molecular neuroimaging investigation was conducted on a 61 years-old female proband diagnosed with PSP. We also collected the clinical presentation data and history of the patient's pedigree, and performed further genetic analysis of 4 relatives, from two generations, with and without symptoms. Results: The proband exhibited typical clinical manifestation of PSP. A cranial MRI revealed midbrain atrophy, and an FDG-PET scan suggested hypo-metabolic changes in caudate nucleus, left prefrontal lobe, both temporal poles, and midbrain. 18F-florzolo-tau-PET revealed tau-protein deposits in the thalamus and brainstem bilaterally. A gene test by whole-exome sequencing identified a novel MAPT variant [NM_005910.6, exon 11, c.1024G > A (p.E342K)], and the same variant was also identified in one affected relative and one asymptomatic relative, a probable pre-symptomatic carrier. Conclusion: The PSP pedigree caused by the novel MAPT (E342K) variant, expanded the mutational spectrum of MAPT.

CPT2 mediated fatty acid oxidation is dispensable for humoral immunity.

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids and fatty acids. While several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. Here, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte specific deletion of CPT2. Stable 13C isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2 deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and antibody production upon either thymus-dependent or -independent antigen challenges. Together, our findings indicate that CPT2 mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

Attention decoupled contrastive learning for semi-supervised segmentation method based on data augmentation.

Objective.Deep learning algorithms have demonstrated impressive performance by leveraging large labeled data. However, acquiring pixel-level annotations for medical image analysis, especially in segmentation tasks, is both costly and time-consuming, posing challenges for supervised learning techniques. Existing semi-supervised methods tend to underutilize representations of unlabeled data and handle labeled and unlabeled data separately, neglecting their interdependencies.Approach.To address this issue, we introduce the Data-Augmented Attention-Decoupled Contrastive model (DADC). This model incorporates an attention decoupling module and utilizes contrastive learning to effectively distinguish foreground and background, significantly improving segmentation accuracy. Our approach integrates an augmentation technique that merges information from both labeled and unlabeled data, notably boosting network performance, especially in scenarios with limited labeled data.Main results.We conducted comprehensive experiments on the automated breast ultrasound (ABUS) dataset and the results demonstrate that DADC outperforms existing segmentation methods in terms of segmentation performance.