Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway.

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aß) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aß plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aß clearance and alleviating AD pathology. ECM remodeling also promoted Aß plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.

Quantitative assessment of the associations between DNA repair gene XRCC3 Thr241Met polymorphism and pancreatic cancer.

BACKGROUND: Prior research exploring the correlation between the XRCC3 Thr241Met polymorphism and the susceptibility to pancreatic cancer has yielded conflicting outcomes. To date, there has been a notable absence of studies examining this polymorphism. The primary aim of the current investigation is to elucidate the potential role of the XRCC3 Thr241Met polymorphism as a risk factor in the development of pancreatic cancer. METHODS: The comprehensive literature search was meticulously conducted across primary databases, including PubMed, Embase, and CNKI (China National Knowledge Infrastructure), spanning from the inception of each database through January 2024. To synthesize the data, a meta-analysis was performed using either a fixed or random-effects model, as appropriate, to calculate the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). RESULTS: The analysis revealed significant associations between the XRCC3 Thr241Met polymorphism and an increased risk of pancreatic cancer. This was evidenced through various genetic model comparisons: allele contrast (T vs. C: OR = 0.77, 95% CI = 0.70-0.86, P < 0.001), homozygote comparison (TT vs. CC: OR = 0.71, 95% CI = 0.58-0.88, P = 0.001), heterozygote comparison (TC vs. CC: OR = 0.67, 95% CI = 0.52-0.87, P = 0.003), and a dominant genetic model (TT/TC vs. CC: OR = 0.68, 95% CI = 0.57-0.81, P < 0.001). Additionally, subgroup analyses based on ethnicity disclosed that these associations were particularly pronounced in the Caucasian population, with all genetic models showing significance (P < 0.05). CONCLUSIONS: The XRCC3 Thr241Met polymorphism has been identified as contributing to a reduced risk of pancreatic cancer in the Caucasian population. This finding underscores the need for further research to validate and expand upon our conclusions, emphasizing the urgency for continued investigations in this domain.

Effect of pharmaceutical promotion and incentives offered by pharmaceutical companies on the prescribing pattern of medical students: a cross-sectional study from a developing nation Pakistan.

Background: Pharmaceutical companies continuously pursue healthcare professionals, starting from the medical college level, which can ultimately lead to irrational prescribing of drugs and antibiotics. Therefore, our main aim was to evaluate the opinions and attitudes of medical students toward pharmaceutical promotion. Methods: This study utilized a cross-sectional online survey that applied the snowball sampling technique. Data were collected from three public and three private sector medical colleges in Punjab, Pakistan using snowball sampling. A modified version of a pre-structured questionnaire was used to collect data between October 2020 and January 2021. Medical students from the third year onward were captivated. The tool was made available on Google Forms and students could access it by clicking the link shared. The effect of promotion on prescribing pattern and future prescribing of antibiotics were measured. Descriptive statistics, chi-square, and t-test were used to analyze the data. Results: A total of 1,301 students filled out the survey, but only 1,227 responses were acceptable. The average age was found to be 23.4 ± 1.59 years. Slightly more than half of the respondents were male participants (57.7%), and a significant proportion (84.1%) reported being aware of pharmaceutical promotion. A smaller number (27.7%) felt that physicians who meet medical representatives more frequently tend to prescribe more antibiotics and 46.3% indicated they would be willing to prescribe antibiotics under the promotional influence. Medical students who were male, in senior college years, attended government institutions, and had lower parental income showed significantly higher perception and attitude scores (p < 0.05) which, in turn, may show their inclination to promotional activities. Many students agreed with the view that pharmaceutical promotion (PP) activities may alter prescribing practices and also believed that they contribute to the increased irrational prescribing of drugs and antibiotics. Conclusion: The study revealed that only a small number of students are willing to engage in promotional activities and accept rewards, which influences their choice toward selection of drugs and antibiotics. This study highlighted the necessity of giving proper educational instructions regarding the promotion of drugs to medical students. This study also focused on the educational prerequisites of the students.

Degradation of sulfamethazine in coastal aquaculture tailwater by Na2S2O4@iron-electrode electrooxidation combined with ceramic membrane process.

Offshore aquaculture's explosive growth improves the public food chain while also unavoidably adding new pollutants to the environment. Consequently, the protection of coastal marine eco-systems depends on the efficient treatment of wastewater from marine aquaculture. For the sulfamethazine (SMZ) of representative sulfonamides and total organic pollutants removal utilizing in-situ high salinity, this work has established an inventive and systematic treatment process coupled with iron-electrode electrochemical and ultrafiltration. Additionally, the activated dithionite (DTN) was being used in the electrochemical and ultrafiltration processes with electricity/varivalent iron (FeII/FeIII) and ceramic membrane (CM), respectively, indicated by the notations DTN@iron-electrode/EO-CM. Quenching experiments and ESR detection have identified plenty of reactive species including SO4·-, ·OH, 1O2, and O2·-, for the advanced treatment. In addition, the mass spectrometry (MS) and the Gaussian simulation calculation for these primary reaction sites revealed the dominate SMZ degradation mechanisms, including cleavage of S-N bond, hydroxylation, and Smile-type rearrangement in DTN@iron-electrode/EO process. The DTN@iron-electrode/EO effluent also demonstrated superior membrane fouling mitigation in terms of the CM process, owing to its higher specific flux. XPS and SEM confirmed the reducing membrane fouling, which showed the formation of a loose and porous cake layer. This work clarified diverse reactive species formation and detoxification with DTN@iron-electrode/EO system and offers a sustainable and efficient process for treating tailwater from coastal aquaculture.

Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.

Gene-editing technology shows great potential in glioblastoma (GBM) therapy. Due to the complexity of GBM pathogenesis, a single gene-editing-based therapy is unlikely to be successful; therefore, a multi-gene knockout strategy is preferred for effective GBM inhibition. Here, a non-invasive, biodegradable brain-targeted CRISPR/Cas12a nanocapsule is used that simultaneously targeted dual oncogenes, EGFR and PLK1, for effective GBM therapy. This cargo nanoencapsulation technology enables the CRISPR/Cas12a system to achieve extended blood half-life, efficient blood-brain barrier (BBB) penetration, active tumor targeting, and selective release. In U87MG cells, the combinatorial gene editing system resulted in 61% and 33% knockout of EGFR and PLK1, respectively. Following systemic administration, the CRISPR/Cas12a system demonstrated promising brain tumor accumulation that led to extensive EGFR and PLK1 gene editing in both U87MG and patient-derived GSC xenograft mouse models with negligible off-target gene editing detected through NGS. Additionally, CRISPR/Cas12a nanocapsules that concurrently targeted the EGFR and PLK1 oncogenes showed superior tumor growth suppression and significantly improved the median survival time relative to nanocapsules containing single oncogene knockouts, signifying the potency of the multi-oncogene targeting strategy. The findings indicate that utilization of the CRISPR/Cas12a combinatorial gene editing technique presents a practical option for gene therapy in GBM.

The relationship between serum coagulation parameters and the recurrence of chronic subdural hematoma.

The aim is to investigate the relationship between serum coagulation parameters (PT, APTT, D-D and FDP) before hospitalization and recurrence of chronic subdural hematoma (CSDH). 236 patients with CSDH who were diagnosed for the first time and had complete medical records were followed up for at least 90 days. Fifty patients (21.2%) had relapsed. Univariate analysis was conducted including general data, imaging data and test results. Serum coagulation parameters (PT, APTT, D-D and FDP) were detected for all CSDH patients. The study identified several factors that exhibited a significant correlation with chronic subdural hematoma (CSDH) recurrence. These factors included advanced age (p = 0.01), hypertension (p = 0.04), liver disease (p = 0.01), anticoagulant drug use (p = 0.01), antiplatelet drug use (p = 0.02), bilateral hematoma (p = 0.02), and single-layer hematoma (p = 0.01). In addition, the presence of fibrin/fibrinogen degradation products (FDP) exceeding 5 mg/L demonstrated a significant relationship with CSDH recurrence (P < 0.05). Notably, the combined assessment of D-dimer (D-D) and FDP exhibited a significant difference, particularly regarding recurrence within 30 days after surgery (P < 0.05). The simultaneous elevation of serum FDP and D-D levels upon admission represents a potentially novel predictor for CSDH recurrence. This finding is particularly relevant for patients who experience recurrence within 30 days following surgical intervention. Older individuals with CSDH who undergo trepanation and drainage should be closely monitored due to their relatively higher recurrence rate.

Time trends and regional variation in utilization of antidiabetic medicines in China, 2015-2022.

AIM: To assess the use of non-insulin antidiabetic medicines in China. MATERIALS AND METHODS: We analysed the national procurement data for 29 non-insulin antidiabetic medicines from nine subgroups in China from 2015 to 2022. We estimated the number of defined daily doses (DDDs) procured per year in seven regions of China for nine subgroups and adjusted the data by the number of patients with diabetes. For each subgroup, the regional ratio was calculated by comparing the procurement per patient in each region with the procurement nationwide. The regional disparity was the difference between the highest and lowest regional ratios. We compared the medication patterns across regions. RESULTS: Nationally, between 2015 and 2022, the number of DDDs per patient increased from 14.45 to 47.37. The two most commonly used categories were sulphonylurea and biguanides, which increased from 7.04 to 15.39 (119%) and 3.28 to 11.11 (239%) DDDs per patient, respectively. The procurement of new drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists) increased quickly and had >5000% relative changes. Particularly for sodium-glucose cotransporter type 2 inhibitors, it increased from 0.08 to 5.03 DDDs (6662%). The southwest region had the highest relative change (319%), while the southern region had the lowest (118%). Biguanide and thiazolidinediones had the lowest (1.19) and highest level (2.21) of regional disparity in 2022, respectively. CONCLUSION: The procurement of non-insulin antidiabetic medicines in China has increased a lot from 2015 to 2022. In terms of DDDs per patient, sulphonylurea ranked first, followed by metformin. The procurement of new drugs increased greatly. A large regional disparity existed in medicine usage and patterns.

Activating transcription factor 6 alleviates secondary brain injury by increasing cystathionine γ-lyase expression in a rat model of intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) comprises primary and secondary injuries, the latter of which induces increased inflammation and apoptosis and is more severe. Activating transcription factor 6 (ATF6) is a type-II transmembrane protein in the endoplasmic reticulum (ER). ATF6 target genes could improve ER homeostasis, which contributes to cryoprotection. Hence, we predict that ATF6 will have a protective effect on brain tissue after ICH. METHOD: The ICH rat model was generated through autologous blood injection into the right basal ganglia, the expression of ATF6 after ICH was determined by WB and IF. The expression of ATF6 was effectively controlled by means of intervention, and a series of measures was used to detect cell death, neuroinflammation, brain edema, blood-brain barrier and other indicators after ICH. Finally, the effects on long-term neural function of rats were measured by behavioral means. RESULT: ATF6 was significantly increased in the ICH-induced brain tissues. Further, ATF6 was found to modulate the expression of cystathionine γ-lyase (CTH) after ICH. Upregulation of ATF6 attenuated neuronal apoptosis and inflammation in ICH rats, along with mitigation of ICH-induced brain edema, blood-brain barrier deterioration, and cognitive behavior defects. Conversely, ATF6 genetic knockdown induced effects counter to those aforementioned. CONCLUSIONS: This study thereby emphasizes the crucial role of ATF6 in secondary brain injury in response to ICH, indicating that ATF6 upregulation may potentially ameliorate ICH-induced secondary brain injury. Consequently, ATF6 could serve as a promising therapeutic target to alleviate clinical ICH-induced secondary brain injuries.

Exploring the thermal decomposition and detonation mechanisms of 2,4-dinitroanisole by TG-FTIR-MS and molecular simulations.

2,4-dinitroanisole (DNAN), an insensitive explosive, has replaced trinitrotoluene (TNT) in many melt-cast explosives to improve the safety of ammunition and becomes a promising material to desensitize novel explosives of high sensitivity. Here, we combine thermogravimetric-Fourier transform infrared spectrometry-Mass spectrometry (TG-FTIR-MS), density functional theory (DFT), and ReaxFF molecular dynamics (MD) to investigate its thermal decomposition and detonation mechanisms. As revealed by TG-FTIR-MS, the thermal decomposition of DNAN starts at ca. 453 K when highly active NO2 is produced and quickly converted to NO resulting in the formation of a large amount of Ph(OH)(OH2)OCH3+. DFT calculations show that the activation energy of DNAN is higher than that of TNT due to the lack of α-H. Further steps in both thermal decomposition and detonation reactions of the DNAN are dominated by bimolecular O-transfers. ReaxFF MD indicates that DNAN has a lower heat of explosion than TNT, in accordance with the observation that the activation energies of polynitroaromatic explosives are inversely proportional to their heat of explosion. The inactive -OCH3 group and less nitro groups also render DNAN higher thermal stability than TNT.

A study on the simultaneous determination of nitrogen content and 15N isotope abundance in plants using peak height intensities at m/z 28 and 29.

A method for simultaneous determination of nitrogen content and 15N isotope abundance in plants was established by Elemental analysis-gas isotope ratio mass spectrometry. Taking poplar leaves and l-glutamic acid as standards, nitrogen content was determined using the standard curve established by weighted least squares regression between the mass of nitrogen element and the total peak height intensity at m/z 28 and 29. Then the 15N isotope abundance was calculated with the peak height intensity at m/z 28 and 29. Through the comparison of several sets of experiments, the impact of mass discrimination effect, tin capsule consumables, isotope memory effect, and the quality of nitrogen on the results were assessed. The results showed that with a weight of 1/x2, the standard curve has a coefficient of determination (R2) of 0.9996. Compared to the traditional Kjeldahl method, the measured nitrogen content deviated less than 0.2 %, and the standard deviation (SD) was less than 0.2 %. Compared to the sodium hypobromite method, the 15N isotopic abundances differed less than 0.2 atom%15N, and the SD was less than 0.2 atom% 15N. The established method offers the advantages of being fast, simple, accurate, and high throughput, providing a novel approach for the simultaneous determination of nitrogen content and 15N isotope abundance in plant samples.

Structural deep multi-view clustering with integrated abstraction and detail.

Deep multi-view clustering, which can obtain complementary information from different views, has received considerable attention in recent years. Although some efforts have been made and achieve decent performances, most of them overlook the structural information and are susceptible to poor quality views, which may seriously restrict the capacity for clustering. To this end, we propose Structural deep Multi-View Clustering with integrated abstraction and detail (SMVC). Specifically, multi-layer perceptrons are used to extract features from specific views, which are then concatenated to form the global features. Besides, a global target distribution is constructed and guides the soft cluster assignments of specific views. In addition to the exploitation of the top-level abstraction, we also design the mining of the underlying details. We construct instance-level contrastive learning using high-order adjacency matrices, which has an equivalent effect to graph attention network and reduces feature redundancy. By integrating the top-level abstraction and underlying detail into a unified framework, our model can jointly optimize the cluster assignments and feature embeddings. Extensive experiments on four benchmark datasets have demonstrated that the proposed SMVC consistently outperforms the state-of-the-art methods.

Escalating Carbon Export from High-Elevation Rivers in a Warming Climate.

High-elevation mountains have experienced disproportionately rapid warming, yet the effect of warming on the lateral export of terrestrial carbon to rivers remains poorly explored and understood in these regions. Here, we present a long-term data set of dissolved inorganic carbon (DIC) and a more detailed, short-term data set of DIC, δ13CDIC, and organic carbon from two major rivers of the Qinghai-Tibetan Plateau, the Jinsha River (JSR) and the Yalong River (YLR). In the higher-elevation JSR with ∼51% continuous permafrost coverage, warming (>3 °C) and increasing precipitation coincided with substantially increased DIC concentrations by 35% and fluxes by 110%. In the lower-elevation YLR with ∼14% continuous permafrost, such increases did not occur despite a comparable extent of warming. Riverine concentrations of dissolved and particulate organic carbon increased with discharge (mobilization) in both rivers. In the JSR, DIC concentrations transitioned from dilution (decreasing concentration with discharge) in earlier, colder years to chemostasis (relatively constant concentration) in later, warmer years. This changing pattern, together with lighter δ13CDIC under high discharge, suggests that permafrost thawing boosts DIC production and export via enhancing soil respiration and weathering. These findings reveal the predominant role of warming in altering carbon lateral export by escalating concentrations and fluxes and modifying export patterns.

Spatial Contraction Based on Velocity Variation for Natural Walking in Virtual Reality.

Virtual Reality (VR) offers an immersive 3D digital environment, but enabling natural walking sensations without the constraints of physical space remains a technological challenge. Previous VR locomotion methods, including game controller, teleportation, treadmills, walking-in-place, and redirected walking (RDW), have made strides towards overcoming this challenge. However, these methods also face limitations such as possible unnaturalness, additional hardware requirements, or motion sickness risks. This paper introduces "Spatial Contraction (SC)", an innovative VR locomotion method inspired by the phenomenon of Lorentz contraction in Special Relativity. Similar to the Lorentz contraction, our SC contracts the virtual space along the user's velocity direction in response to velocity variation. The virtual space contracts more when the user's speed is high, whereas minimal or no contraction happens at low speeds. We provide a virtual space transformation method for spatial contraction and optimize the user experience in smoothness and stability. Through SC, VR users can effectively traverse a longer virtual distance with a shorter physical walking. Different from locomotion gains, the spatial contraction effect is observable by the user and aligns with their intentions, so there is no inconsistency between the user's proprioception and visual perception. SC is a general locomotion method that has no special requirements for VR scenes. The experimental results of our live user studies in various virtual scenarios demonstrate that SC has a significant effect in reducing both the number of resets and the physical walking distance users need to cover. Furthermore, experiments have also demonstrated that SC has the potential for integration with existing locomotion techniques such as RDW.

BiRD: Using Bidirectional Rotation Gain Differences to Redirect Users during Back-and-forth Head Turns in Walking.

Redirected walking (RDW) facilitates user navigation within expansive virtual spaces despite the constraints of limited physical spaces. It employs discrepancies between human visual-proprioceptive sensations, known as gains, to enable the remapping of virtual and physical environments. In this paper, we explore how to apply rotation gain while the user is walking. We propose to apply a rotation gain to let the user rotate by a different angle when reciprocating from a previous head rotation, to achieve the aim of steering the user to a desired direction. To apply the gains imperceptibly based on such a Bidirectional Rotation gain Difference (BiRD), we conduct both measurement and verification experiments on the detection thresholds of the rotation gain for reciprocating head rotations during walking. Unlike previous rotation gains which are measured when users are turning around in place (standing or sitting), BiRD is measured during users' walking. Our study offers a critical assessment of the acceptable range of rotational mapping differences for different rotational orientations across the user's walking experience, contributing to an effective tool for redirecting users in virtual environments.

Effects of topography and stand spatial structure on the diameter at breast height growth of major pioneer tree species of natural broad-leaved mixed forests in Zhejiang Province, China.

Based on the continuous inventory data of forest resources in Zhejiang Province in 2019 and 2021, we used statistical methods such as polynomial regression to analyze the impacts of topography and forest spatial structure on average annual diameter at breast height (DBH) growth of main pioneer tree species in natural broad-leaved mixed forests. The results showed that DBH of Schima superba, Quercus glauca, Quercus fabri, Lithocarpus glaber, Castanopsis eyrei, and Castanopsis sclerophylla were between 5-50.8, 5-41.5, 5-50.8, 5-43.9, 5-55.5, and 5-46.1 cm, respectively. We classified all the trees into three classes based on DBH: small (6-12 cm), medium (12-14 cm), and large (>26 cm). The average annual DBH growth of S. superba and Q. glauca was the highest on semi-shady slope and shady slope, with increases of 2.9%-15.7% and 1.1%-41.2%, respectively. The average annual DBH growth of large-diameter S. superba, L. glaber, C. eyrei and C. sclerophylla decreased with the increase of slope, with a maximum decrease of 27.0% for S. superba, with no significant difference among small- and medium-diameter trees as a whole. The slope position did not affect the annual DBH growth of small-diameter trees, while that of medium- and large-diameter S. superba, Q. glauca, and large-diameter Q. fabri, L. glaber decreased with the change of slope position from downhill, mesoslope, uphill to ridge, with a maximum decrease of 28.1% for L. glabe, and the major-diameter C. eyrei was on the contrary. Appropriate increase in the mingling was beneficial to the average annual DBH growth of medium- and large-diameter trees. Moderate mixing was suitable for S. superba, while low degree mixing and moderate mixing was suitable for Q. glauca, Q. fabri and L. glaber, and intensive mixing was suitable for C. eyrei and C. sclerophylla. No significant difference was observed for minor-diameter trees under the mingling. The neighborhood comparison only had a significant effect on the average annual DBH growth of large-diameter Q. glauca, Q. fabri, and L. glaber, which was significantly higher under subdominance-moderation than moderation-inferiority. The average annual DBH growth in the study area was mainly affected by aspect and mixing degree.

Contributions of Chinese hamster ovary cell derived extracellular vesicles and other cellular materials to hollow fiber filter fouling during perfusion manufacturing of monoclonal antibodies.

Hollow fiber filter fouling is a common issue plaguing perfusion production process for biologics therapeutics, but the nature of filter foulant has been elusive. Here we studied cell culture materials especially Chinese hamster ovary (CHO) cell-derived extracellular vesicles in perfusion process to determine their role in filter fouling. We found that the decrease of CHO-derived small extracellular vesicles (sEVs) with 50-200 nm in diameter in perfusion permeates always preceded the increase in transmembrane pressure (TMP) and subsequent decrease in product sieving, suggesting that sEVs might have been retained inside filters and contributed to filter fouling. Using scanning electron microscopy and helium ion microscopy, we found sEV-like structures in pores and on foulant patches of hollow fiber tangential flow filtration filter (HF-TFF) membranes. We also observed that the Day 28 TMP of perfusion culture correlated positively with the percentage of foulant patch areas. In addition, energy dispersive X-ray spectroscopy-based elemental mapping microscopy and spectroscopy analysis suggests that foulant patches had enriched cellular materials but not antifoam. Fluorescent staining results further indicate that these cellular materials could be DNA, proteins, and even adherent CHO cells. Lastly, in a small-scale HF-TFF model, addition of CHO-specific sEVs in CHO culture simulated filter fouling behaviors in a concentration-dependent manner. Based on these results, we proposed a mechanism of HF-TFF fouling, in which filter pore constriction by CHO sEVs is followed by cake formation of cellular materials on filter membrane.

GLFNet: Global-local fusion network for the segmentation in ultrasound images.

Ultrasound imaging, as a portable and radiation-free modality, presents challenges for accurate segmentation due to the variability of lesions and the similar intensity values of surrounding tissues. Current deep learning approaches leverage convolution for extracting local features and self-attention for handling global dependencies. However, traditional CNNs are spatially local, and Vision Transformers lack image specific bias and are computationally demanding. In response, we propose the Global-Local Fusion Network (GLFNet), a hybrid structure addressing the limitations of both CNNs and Vision Transformers. The GLFNet, featuring Global-Local Fusion Blocks (GLFBlocks), integrates global semantic information with local details to improve segmentation. Each GLFBlock comprises Global and Local Branches for feature extraction in parallel. Within the Global and Local Branches, we introduce the Self-Attention Convolution Fusion Block (SACFBlock), which includes a Spatial-Attention Module and Channel-Attention Module. Experimental results show that our proposed GLFNet surpasses its counterparts in the segmentation tasks, achieving the overall best results with an mIoU of 79.58% and Dice coefficient of 74.62% in the DDTI dataset, an mIoU of 76.61% and Dice coefficient of 71.04% in the BUSI dataset, and an mIoU of 86.77% and Dice coefficient of 87.38% in the BUID dataset. The fusion of local and global features contributes to enhanced performance, making GLFNet a promising approach for ultrasound image segmentation.

Efficient CRISPR genome editing and integrative genomic analyses reveal the mosaicism of Cas-induced mutations and pleiotropic effects of scarlet gene in an emerging model system.

Despite the revolutionary impacts of CRISPR-Cas gene editing systems, the effective and widespread use of CRISPR technologies in emerging model organisms still faces significant challenges. These include the inefficiency in generating heritable mutations at the organismal level, limited knowledge about the genomic consequences of gene editing, and an inadequate understanding of the inheritance patterns of CRISPR-Cas-induced mutations. This study addresses these issues by 1) developing an efficient microinjection delivery method for CRISPR editing in the microcrustacean Daphnia pulex; 2) assessing the editing efficiency of Cas9 and Cas12a nucleases, examining mutation inheritance patterns, and analyzing the local and global mutation spectrum in the scarlet mutants; and 3) investigating the transcriptomes of scarlet mutants to understand the pleiotropic effects of scarlet underlying their swimming behavior changes. Our reengineered CRISPR microinjection method results in efficient biallelic editing with both nucleases. While indels are dominant in Cas-induced mutations, a few on-site large deletions (>1kb) are observed, most likely caused by microhomology-mediated end joining repair. Knock-in of a stop codon cassette to the scarlet locus was successful, despite complex induced mutations surrounding the target site. Moreover, extensive germline mosaicism exists in some mutants, which unexpectedly produce different phenotypes/genotypes in their asexual progenies. Lastly, our transcriptomic analyses unveil significant gene expression changes associated with scarlet knock-out and altered swimming behavior in mutants, including several genes (e.g., NMDA1, ABAT, CNTNAP2) involved in human neurodegenerative diseases. This study expands our understanding of the dynamics of gene editing in the tractable model organism Daphnia and highlights its promising potential as a neurological disease model.