Segmentation and Multi-Timepoint Tracking of 3D Cancer Organoids from Optical Coherence Tomography Images Using Deep Neural Networks.

Recent years have ushered in a transformative era in in vitro modeling with the advent of organoids, three-dimensional structures derived from stem cells or patient tumor cells. Still, fully harnessing the potential of organoids requires advanced imaging technologies and analytical tools to quantitatively monitor organoid growth. Optical coherence tomography (OCT) is a promising imaging modality for organoid analysis due to its high-resolution, label-free, non-destructive, and real-time 3D imaging capabilities, but accurately identifying and quantifying organoids in OCT images remain challenging due to various factors. Here, we propose an automatic deep learning-based pipeline with convolutional neural networks that synergistically includes optimized preprocessing steps, the implementation of a state-of-the-art deep learning model, and ad-hoc postprocessing methods, showcasing good generalizability and tracking capabilities over an extended period of 13 days. The proposed tracking algorithm thoroughly documents organoid evolution, utilizing reference volumes, a dual branch analysis, key attribute evaluation, and probability scoring for match identification. The proposed comprehensive approach enables the accurate tracking of organoid growth and morphological changes over time, advancing organoid analysis and serving as a solid foundation for future studies for drug screening and tumor drug sensitivity detection based on organoids.

Secure high-density constellation mapping OTFS modulation scheme with low PAPR.

In this paper, a secure orthogonal time-frequency space (OTFS) modulation transmission system based on 3D dense constellation mapping (DCM) geometric shaping is proposed, and a selective reduction amplitude algorithm (SRA) for DCM to reduce peak average power ratio (PAPR) is presented. The DCM is based on regular tetrahedron construction to improve its space utilization efficiency. The proposed SRA involves reducing high PAPRs transmitter and restoring them at the receiving end, which only requires an additional 0.57% of the total transmission capacity. The algorithm reduces PAPR while ensuring the bit error rate performance of the system, so it is suitable for systems that need to process large amounts of transmitted data quickly. By verifying the actual transmission performance on a 2 km of 7-core optical fiber transmission system, the optical transmission with a bit rate of 33.93Gb/s is achieved. The experimental results show that when the bit error rate (BER) reaches the 3.8×10-3 threshold, the OTFS system using DCM and SRA could improve the receiver sensitivity by 3.7 dB compared with the OTFS system using concentric cube mapping and SRA, and 2.7 dB compared with the OFDM system using DCM. After adding the SRA, the PAPR of the OTFS system is reduced by more than 2.2 dB. When the received optical power reaches near the bit error rate threshold, the SRA valid data can be fully recovered by optimizing the SRA.

Advancing Neurological Health: Insights into Aging, Immunity, and Vascular Dynamics.

This editorial provides an overview of recent advancements in the understanding and treatment of neurological disorders, focusing on aging, immunity, and blood flow, as featured in this special issue. The first section explores the importance of identifying biomarkers of aging and aging-related diseases, such as Alzheimer's Disease, highlighting the emerging role of saliva-based biomarkers and the gut-brain axis in disease diagnosis and management. In the subsequent section, the dysregulated immune systems associated with aging are discussed, emphasizing the intricate landscape of the immune system during aging and its bidirectional relationship with neuroinflammation. Additionally, insights into the involvement of Myeloid-Derived Suppressor Cells (MDSCs) in Multiple Sclerosis (MS) pathogenesis are presented. The third section examines the role of microglia in neuroinflammation and various neurological diseases, including age-related macular degeneration (AMD) and Tuberculous Meningitis (TBM). Furthermore, the therapeutic potential of stem cell and extracellular vesicle-based therapies for stroke is explored, along with molecular mechanism of how inflammation regulates cerebral and myocardial ischemia. Finally, the importance of blood flow in maintaining vascular health and its impact on neurological disorders are discussed, highlighting the potential of novel assessment methods for optimizing patient care. Overall, this special issue offers valuable insights into the complex mechanisms underlying neurological disorders and identifies potential avenues for therapeutic intervention.

An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk subset of Ph-like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph-like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling (CRLF2/EPOR/JAK2 rearrangements or p-CRKL/p-STAT5 high expression) had the worst outcome (3-year overall survival [OS] of 28.8% vs. 80.1% for others, p < 0.001; 2-year event-free survival [EFS] of 6.5% vs. 57.0% for others, p < 0.001). Multivariable analysis demonstrated that this high-risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35-8.81, p < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99-5.39, p < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.

STAT5 phosphorylation plus minimal residual disease defines a novel risk classification in adult B-cell acute lymphoblastic leukaemia.

The dysregulation of the Janus family tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) is closely related to acute lymphoblastic leukaemia (ALL), whereas the clinical value of phosphorylated STAT5 (pSTAT5) remains elusive. Herein we performed a prospective study on clinical significance of flow cytometry-based pSTAT5 in adult B-ALL patients. A total of 184 patients were enrolled in the Precision-Classification-Directed-Target-Total-Therapy (PDT)-ALL-2016 cohort between January 2018 and December 2021, and STAT5 phosphorylation was detected by flow cytometry at diagnosis. Based on flow-pSTAT5, the population was classified into pSTAT5low (113/184, 61.1%) and pSTAT5high (71/184, 38.9%). Overall survival (OS) and event-free survival (EFS) were inferior in pSTAT5high patients than in those with pSTAT5low (OS, 44.8% vs. 65.2%, p = 0.004; EFS, 23.5% vs. 52.1%, p < 0.001), which was further confirmed in an external validation cohort. Furthermore, pSTAT5 plus flow-based minimal residual disease (MRD) postinduction defines a novel risk classification as being high risk (HR, pSTAT5high + MRD+), standard risk (SR, pSTAT5low + MRD-) and others as moderate-risk group. Three identified patient subgroups are distinguishable with disparate survival curves (3-year OS rates, 36.5%, 56.7% and 76.3%, p < 0.001), which was confirmed on multivariate analysis (hazard ratio 3.53, p = 0.003). Collectively, our study proposed a novel, simple and flow-based risk classification by integrating pSTAT5 and MRD in favour of risk-guided treatment for B-ALL.

Ultrasound-induced reorientation for multi-angle optical coherence tomography.

Organoid and spheroid technology provide valuable insights into developmental biology and oncology. Optical coherence tomography (OCT) is a label-free technique that has emerged as an excellent tool for monitoring the structure and function of these samples. However, mature organoids are often too opaque for OCT. Access to multi-angle views is highly desirable to overcome this limitation, preferably with non-contact sample handling. To fulfil these requirements, we present an ultrasound-induced reorientation method for multi-angle-OCT, which employs a 3D-printed acoustic trap inserted into an OCT imaging system, to levitate and reorient zebrafish larvae and tumor spheroids in a controlled and reproducible manner. A model-based algorithm was developed for the physically consistent fusion of multi-angle data from a priori unknown angles. We demonstrate enhanced penetration depth in the joint 3D-recovery of reflectivity, attenuation, refractive index, and position registration for zebrafish larvae, creating an enabling tool for future applications in volumetric imaging.

Mutations of epigenetic modifier genes predict poor outcome in adult acute lymphoblastic leukemia.

Epigenetic modifier (EM) genes play important roles in the occurrence and progression of acute lymphoblastic leukemia (ALL). However, the prognostic significance of EM mutations in ALL has not yet been thoroughly investigated. This retrospective study included 205 adult patients with ALL engaged in a pediatric-type regimen. Based on targeted next-generation sequencing, they were divided into EM mutation group (EM-mut, n = 75) and EM wild-type group (EM-wt, n = 130). The EM-mut group showed a higher positive rate of minimal residual disease (MRD) on treatment day24 and before consolidation therapy (P = 0.026, 0.020). Multivariate Cox regression analysis showed that EM-mut was an independent adverse factor for overall survival (OS) and event-free survival (EFS) (HR = 2.123, 1.742; P = 0.009, 0.007). Survival analysis revealed that the OS and EFS rates were significantly lower in the EM-mut group than in the EM-wt group (3-year OS rate, 45.8% vs. 65.0%, P = 0.0041; 3-year EFS rate, 36.7% vs. 53.2%, P = 0.011). In conclusion, EM was frequently mutated in adult ALL and was characterized by poor response to induction therapy and inferior clinical outcomes.

Hemorrhagic stroke-induced subtype of inflammatory reactive astrocytes disrupts blood-brain barrier.

Astrocytes undergo disease-specific transcriptomic changes upon brain injury. However, phenotypic changes of astrocytes and their functions remain unclear after hemorrhagic stroke. Here we reported hemorrhagic stroke induced a group of inflammatory reactive astrocytes with high expression of Gfap and Vimentin, as well as inflammation-related genes lipocalin-2 (Lcn2), Complement component 3 (C3), and Serpina3n. In addition, we demonstrated that depletion of microglia but not macrophages inhibited the expression of inflammation-related genes in inflammatory reactive astrocytes. RNA sequencing showed that blood-brain barrier (BBB) disruption-related gene matrix metalloproteinase-3 (MMP3) was highly upregulated in inflammatory reactive astrocytes. Pharmacological inhibition of MMP3 in astrocytes or specific deletion of astrocytic MMP3 reduced BBB disruption and improved neurological outcomes of hemorrhagic stroke mice. Our study demonstrated that hemorrhagic stroke induced a group of inflammatory reactive astrocytes that were actively involved in disrupting BBB through MMP3, highlighting a specific group of inflammatory reactive astrocytes as a critical driver for BBB disruption in neurological diseases.

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke.

The crosstalk between reactive astrocytes and infiltrated immune cells plays a critical role in maintaining blood-brain barrier (BBB) integrity. However, how astrocytes interact with immune cells and the effect of their interaction on BBB integrity after hemorrhagic stroke are still unclear. By performing RNA sequencing in astrocytes that were activated by interleukin-1α (IL-1α), tumor necrosis factor α (TNFα), and complement component 1q (C1q) treatment, we found CCL5 was among the top upregulated genes. Immunostaining and western blot results demonstrated that CCL5 was increased in mice brain after hemorrhagic stroke. Flow cytometry showed that knockout of astrocytic CCL5 reduced the infiltration of CD8+ but not CD4+ T and myeloid cells into the brain (p < 0.05). In addition, knockout CCL5 in astrocytes increased tight junction-related proteins ZO-1 and Occludin expression; reduced Evans blue leakage, perforin and granzyme B expression; improved neurobehavioral outcomes in hemorrhagic stroke mice (p < 0.05), while transplantation of CD8+ T cells reversed these protective effects. Moreover, co-culture of CD8+ T cells with bEnd.3 cells induced the apoptosis of bEnd.3 cells, which was rescued by inhibiting perforin. In conclusion, our study suggests that CCL5 mediated crosstalk between astrocytes and CD8+ T cells represents an important therapeutic target for protecting BBB in stroke.

Constructing mesoporous biochar derived from waste carton: Improving multi-site adsorption of dye wastewater and investigating mechanism.

The development of cost-efficient biochar adsorbent with a simple preparation method is essential to constructing efficient wastewater treatment system. Here, a low-cost waste carton biochar (WCB) prepared by a simple two-step carbonization was applied in efficiently removing Rhodamine B (RhB) in aqueous environment. The maximum ability of WCB for RhB adsorption was 222 mg/g, 6 and 10 times higher than both of rice straw biochar (RSB) and broadbean shell biochar (BSB), respectively. It was mainly ascribed to the mesopore structure (3.0-20.4 nm) of WCB possessing more spatial sites compared to RSB (2.2 nm) and BSB (2.4 nm) for RhB (1.4 nm✕1.1 nm✕0.6 nm) adsorption. Furthermore, external mass transfer (EMT) controlled mass transfer resistance (MTR) of the RhB sorption process by WCB which was fitted with the Langmuir model well. Meanwhile, the adsorption process was dominated by physisorption through van der Waals forces and π-π interactions. A mixture of three dyes in river water was well removed by using WCB. This work provides a straightforward method of preparing mesoporous biochar derived from waste carton with high-adsorption capacity for dye wastewater treatment.

Prognostic impact of TP53 mutations in adult acute lymphoblastic leukemia treated with a pediatric-type regimen.

The prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remains debatable. Herein, we determined the clinical significance of TP53mut in 283 adult ALL patients treated with a pediatric-type regimen. TP53mut were found in 11.0% (31) of patients, including 19 cases in adolescent and young adult (AYA) patients and 12 cases in non-AYA patients. Patients with TP53mut had poorer overall survival (OS) and event-free survival (EFS) in the non-AYA subgroup (n = 64) (3-year OS, 18.2% vs 50.9%, p = .0033; 3-year EFS, 0 vs 45.3%, p = .00028). however, this had to be taken cautiously due to a limited number of patients. In the AYA subgroup (n = 219), TP53mut did not impact OS or EFS (3-year OS, 60.6%vs71.0%, p = .55; 3-year EFS, 52.5%vs59.6%, p = .57). Collectively, our data reveal that the pediatric-type regimen eliminated the poor prognostic impact of TP53mut in AYA ALL. However, in non-AYA ALL patients, TP53mut remain a potential biomarker associated with poor outcomes.

Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.

Removal effect of typical pollutants from stormwater runoff in ecological ditches.

Ecological ditches are a typical ecological facility for controlling road stormwater runoff pollution; they mainly remove harmful pollutants from runoff through plant absorption, retention and sedimentation, ecological adsorption, and microbial action. In this paper, according to the transport form of rainwater in the ditches, the removal effects of two different types of ditches on nitrogen, phosphorus, heavy metals, and other pollutants were simulated under three conditions of rainfall, slow flow, and still water, respectively, and their operating characteristics were analyzed. The results showed that the removal rate of TN in the two ecological ditches under slow flow conditions showed a downward trend as a whole with the increase of hydraulic load, and the suitable hydraulic load for TN removal should be selected as 0.3 m3/(m2 day). Under the simulated rainfall conditions, the TN removal rates of no. 1 and no. 2 ditches were 26.1-37.2% and 24.9 ~ 52.5%, respectively, and the TP removal rates were 44.6 ~ 63.3% and 36.1 ~ 62.1%. After 19.4 h and 22.1 h in the static state, the TP concentration in no. 1 ditch and no. 2 ditch reached the surface V water standard, and the average removal rate of TP was 74.7% and 53.7%, respectively. This paper provides a reference for selecting suitable parameters and optimizing the operational performance of ecological ditches to reduce runoff pollutants more effectively.

Ultra-high-resolution optical coherence tomography for the investigation of thin multilayered pharmaceutical coatings.

Optical Coherence Tomography (OCT) has recently gained attention as a promising technology for in-line monitoring of pharmaceutical film-coating processes for (single-layered) tablet coatings and end-point detection with commercial systems. An increasing interest in the investigation of multiparticulate dosage forms with mostly multi-layered coatings below 20 µm final film thickness demands advancement in OCT technology for pharmaceutical imaging. We present an ultra-high-resolution (UHR-) OCT and investigate its performance based on three different multiparticulate dosage forms with different layer structures (one single-layered, two multi-layered) with layer thicknesses in a range from 5 to 50 µm. The achieved system resolution of 2.4 µm (axial) and 3.4 µm (lateral, both in air) enables the assessment of defects, film thickness variability and morphological features within the coating, previously unattainable using OCT. Despite the high transverse resolution, the provided depth of field was found sufficient to reach the core region of all dosage forms under test. We further demonstrate an automated segmentation and evaluation of UHR-OCT images for coating thicknesses, where human experts struggle using today's standard OCT systems.

Biorefining of rapeseed meal: A new and sustainable strategy for improving Cr(VI) biosorption on residual wastes from agricultural byproducts after phenolic extraction.

Phenolic recovery from agricultural byproducts has been highlighted due to their health-promoting bioactivities. However, uncontrolled discard of residues after extraction process would induce environmental pollution and bioresource waste. In this study, biorefining of phenolic-rich rapeseed meal (RSM) and its defatted sample (dRSM) was attempted by holistic utilization of phenolic extract and residue separately. Phenolic removal could significantly improve residues' Cr(VI) adsorption capacities by about 21%, which presented extended physical surface and more released functional groups. Moreover, simulating raw material by remixing 3% separated phenolic extracts or main component sinapic acid therein with corresponding residues further improved about 12% adsorption efficiencies. These indicated that the different present forms of phenolics had opposite effects on Cr(VI) removal. While natural conjugational form inhibited hosts' biosorption, free form had enhanced functions for either extract or residue. Four optimal adsorption parameters (pH, adsorbent dosage, contact time and initial Cr(VI) concentration), three kinetic (pseudo-first order, pseudo-second order and intra-particle diffusion) models and two isotherms (Langmuir and Freundlich) were used to reveal the adsorption process. The maximum Cr(VI) adsorption capacity on residues could reach about 100 mg/g, which was superior to that of most biosorbents derived from agricultural byproducts, even some biochar. Together with the residues' advantages with everlasting capacity after 3 adsorption-desorption cycles and excellent abilities for adsorbing multiple co-existed metal ions (Cr(VI), Cd(II), Cu(II), Pb(II), Ni(II) and Zn(II)), phenolic recovery was first proved to be a new and sustainable strategy for modifying biosorbents from agricultural byproducts with zero waste.

Roles of Ependymal Cells in the Physiology and Pathology of the Central Nervous System.

Ependymal cells are indispensable components of the central nervous system (CNS). They originate from neuroepithelial cells of the neural plate and show heterogeneity, with at least three types that are localized in different locations of the CNS. As glial cells in the CNS, accumulating evidence demonstrates that ependymal cells play key roles in mammalian CNS development and normal physiological processes by controlling the production and flow of cerebrospinal fluid (CSF), brain metabolism, and waste clearance. Ependymal cells have been attached to great importance by neuroscientists because of their potential to participate in CNS disease progression. Recent studies have demonstrated that ependymal cells participate in the development and progression of various neurological diseases, such as spinal cord injury and hydrocephalus, raising the possibility that they may serve as a potential therapeutic target for the disease. This review focuses on the function of ependymal cells in the developmental CNS as well as in the CNS after injury and discusses the underlying mechanisms of controlling the functions of ependymal cells.

Successful endovascular thrombectomy 8 days after onset of acute ischemic stroke: A case report.

Endovascular thrombectomy (EVT) is the recommended option for acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) that within 6 h onset of stroke. The EVT treatment time window has been extended to 24 h in carefully selected patients by DAWN trial. Recent evidences indicated that some patients presented beyond 24 h still potentially benefit from EVT treatment. Herein, we describe one case of successful delayed EVT in a 50-year-old male AIS patient with an 8-day history of left middle cerebral artery occlusion. Before surgery, CT perfusion demonstrated a marked left hypoperfusion with penumbra volume of 127 mL and ischemic core volume of 10 mL. EVT was performed with complete recanalization and significant improvement in his neurological deficits at 90-days post-surgery follow-up. In future, more randomized clinical trials are warranted to further confirm the safety, efficacy, as well as the applicable population of delayed EVT.

The roles of microglia and astrocytes in myelin phagocytosis in the central nervous system.

Myelination is an important process in the central nervous system (CNS). Oligodendrocytes (OLs) extend multiple layers to densely sheath on axons, composing the myelin to achieve efficient electrical signal conduction. The myelination during developmental stage maintains a balanced state. However, numerous CNS diseases including neurodegenerative and cerebrovascular diseases cause demyelination and disrupt the homeostasis, resulting in inflammation and white matter deficits. Effective clearance of myelin debris is needed in the region of demyelination, which is a key step for remyelination and tissue regeneration. Microglia and astrocytes are the major resident phagocytic cells in the brain, which may play different or collaborative roles in myelination. Microglia and astrocytes participate in developmental myelination through engulfing excessive unneeded myelin. They are also involved in the clearance of degenerated myelin debris for accelerating remyelination, or engulfing healthy myelin sheath for inhibiting remyelination. This review focuses on the roles of microglia and astrocytes in phagocytosing myelin in the developmental brain and diseased brain. In addition, the interaction between microglia and astrocytes to mediate myelin engulfment is also summarized.

Can nature help limit warming below 1.5°C?

Nature-based efforts could further climate mitigation and help limit warming to 1.5°C, given that proper and immediate solutions are implemented with similar ambition as in energy and industry sectors; however, omission of natural solutions or delays in overall climate action would substantially undermine the climate target of Paris Agreement.

Scene-dependent, feedforward eye gaze metrics can differentiate technical skill levels of trainees in laparoscopic surgery.

INTRODUCTION: In laparoscopic surgery, looking in the target areas is an indicator of proficiency. However, gaze behaviors revealing feedforward control (i.e., looking ahead) and their importance have been under-investigated in surgery. This study aims to establish the sensitivity and relative importance of different scene-dependent gaze and motion metrics for estimating trainee proficiency levels in surgical skills. METHODS: Medical students performed the Fundamentals of Laparoscopic Surgery peg transfer task while recording their gaze on the monitor and tool activities inside the trainer box. Using computer vision and fixation algorithms, five scene-dependent gaze metrics and one tool speed metric were computed for 499 practice trials. Cluster analysis on the six metrics was used to group the trials into different clusters/proficiency levels, and ANOVAs were conducted to test differences between proficiency levels. A Random Forest model was trained to study metric importance at predicting proficiency levels. RESULTS: Three clusters were identified, corresponding to three proficiency levels. The correspondence between the clusters and proficiency levels was confirmed by differences between completion times (F2,488 = 38.94, p < .001). Further, ANOVAs revealed significant differences between the three levels for all six metrics. The Random Forest model predicted proficiency level with 99% out-of-bag accuracy and revealed that scene-dependent gaze metrics reflecting feedforward behaviors were more important for prediction than the ones reflecting feedback behaviors. CONCLUSION: Scene-dependent gaze metrics revealed skill levels of trainees more precisely than between experts and novices as suggested in the literature. Further, feedforward gaze metrics appeared to be more important than feedback ones at predicting proficiency.