The proactive and reactive mechanisms of learned spatial suppression.

Selection history refers to the notion that previous allocations of attention or suppression have the potential to elicit lingering and enduring selection biases that are isolated from goal-driven or stimulus-driven attention. However, in the singleton detection mode task, manipulating the selection history of distractors cannot give rise to pure proactive inhibition. Therefore, we employed a combination of a working memory task and a feature search mode task, simultaneously recording cortical activity using EEG, to investigate the mechanisms of suppression guided by selection history. The results from event-related potential and reaction times showed an enhanced inhibitory performance when the distractor was presented at the high-probability location, along with instances where the target appeared at the high-probability location of distractors. These findings demonstrate that a generalized proactive inhibition bias is learned and processed independent of cognitive resources, which is supported by selection history. In contrast, reactive rejection toward the low-probability location was evident through the Pd component under varying cognitive resource conditions. Taken together, our findings indicated that participants learned proactive inhibition when the distractor was at the high-probability location, whereas reactive rejection was involved at low-probability location.

Impaired visual-motor functional connectivity in first-episode medication-naïve patients with major depressive disorder.

The perceptual dysfunctions have been fundamental causes of cognitive and emotional problems in patients with major depressive disorder. However, visual system impairment in depression has been underexplored. Here, we explored functional connectivity in a large cohort of first-episode medication-naïve patients with major depressive disorder (n = 190) and compared it with age- and sex-matched healthy controls (n = 190). A recently developed individual-oriented approach was applied to parcellate the cerebral cortex into 92 regions of interest using resting-state functional magnetic resonance imaging data. Significant reductions in functional connectivities were observed between the right lateral occipitotemporal junction within the visual network and 2 regions of interest within the sensorimotor network in patients. The volume of right lateral occipitotemporal junction was also significantly reduced in major depressive disorder patients, indicating that this visual region is anatomically and functionally impaired. Behavioral correlation analysis showed that the reduced functional connectivities were significantly associated with inhibition control in visual-motor processing in patients. Taken together, our data suggest that functional connectivity between visual network and sensorimotor network already shows a significant reduction in the first episode of major depressive disorder, which may interfere with the inhibition control in visual-motor processing. The lateral occipitotemporal junction may be a hub of disconnection and may play a role in the pathophysiology of major depressive disorder.

Identification and validation of CRLF1 and NRG1 as immune-related signatures in hypertrophic scar.

BACKGROUND: Hypertrophic scar (HTS) is a prevalent chronic inflammatory skin disorder characterized by abnormal proliferation and extracellular matrix deposition and the precise mechanisms underlying HTS remain elusive. This study aimed to identify and validate potential immune-related genes associated with hypertrophic scar formation. METHODS: Skin samples from normal (n = 12) and hypertrophic scar tissues (n = 12) were subjected to RNA-seq analysis. Differentially expressed genes (DEGs) and significant modular genes in Weighted gene Co-expression Network Analysis (WGCNA) were identified. Subsequently, functional enrichment analysis was performed on the intersecting genes. Additionally, eight immune-related genes were matched from the ImmPort database. Validation of NRG1 and CRLF1 was carried out using an external cohort (GSE136906). Furthermore, the association between these two genes and immune cells was assessed by Spearman correlation analysis. Finally, RNA was extracted from normal and hypertrophic scar samples, and RT-qPCR, Immunohistochemistry staining and Western Blot were employed to validate the expression of characteristic genes. RESULTS: A total of 940 DEGs were identified between HTS and normal samples, and 288 key module genes were uncovered via WGCNA. Enrichment analysis in key module revealed involvement in many immune-related pathways, such as Th17 cell differentiation, antigen processing and presentation and B cell receptor signaling pathway. The eight immune-related genes (IFI30, NR2F2, NRG1, ESM1, NFATC2, CRLF1, COLEC12 and IL6) were identified by matching from the ImmPort database. Notably, we observed that activated mast cell positively correlated with CRLF1 expression, while CD8 T cells exhibited a positive correlation with NRG1. The expression of NRG1 and CRLF1 was further validated in clinical samples. CONCLUSION: In this study, two key immune-related genes (CRLF1 and NRG1) were identified as characteristic genes associated with HTS. These findings provide valuable insights into the immune-related mechanisms underlying hypertrophic scar formation.

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

NADPH oxidase overexpression and mitochondrial OxPhos impairment are more profound in human hearts donated after circulatory death than brain death.

This study investigated cardiac stress and mitochondrial oxidative phosphorylation (OxPhos) in human donation after circulatory death (DCD) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them with that of human brain death donor (DBD) hearts. A total of 24 human hearts were procured for the research study-6 in the DBD group and 18 in the DCD group. DCD group was divided into three groups (n = 6) based on different WITs (20, 40, and 60 min). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 h. Left ventricular biopsies were performed at hours 0, 2, 4, and 6. Cardiac stress [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits: 47-kDa protein of phagocyte oxidase (p47phox), 91-kDa glycoprotein of phagocyte oxidase (gp91phox)] and mitochondrial oxidative phosphorylation [OxPhos, complex I (NADH dehydrogenase) subunit of ETC (CI)-complex V (ATP synthase) subunit of ETC (CV)] proteins were measured in cardiac tissue and mitochondria respectively. Modulation of cardiac stress and mitochondrial dysfunction were observed in both DCD and DBD hearts. However, DCD hearts suffered more cardiac stress (overexpressed NADPH oxidase subunits) and diminished mitochondrial OxPhos than DBD hearts. The severity of cardiac stress and impaired oxidative phosphorylation in DCD hearts correlated with the longer WIT and subsequent cold storage time. More drastic changes were evident in DCD hearts with a WIT of 60 min or more. Activation of NADPH oxidase via overproduction of p47phox and gp91phox proteins in cardiac tissue may be responsible for cardiac stress leading to diminished mitochondrial oxidative phosphorylation. These protein changes can be used as biomarkers for myocardium damage and might help assess DCD and DBD heart transplant suitability.NEW & NOTEWORTHY First human DCD heart research studied cardiac stress and mitochondrial dysfunction concerning WIT and the efficacy of del Nido cardioplegia as an organ procurement solution and subsequent cold storage. Mild to moderate cardiac stress and mitochondrial dysfunction were noticed in DCD hearts with WIT 20 and 40 min and cold storage for 4 and 2 h, respectively. These changes can serve as biomarkers, allowing interventions to preserve mitochondria and extend WIT in DCD hearts.

Myricetin reduces platelet PANoptosis in sepsis to delay disseminated intravascular coagulation.

Sepsis is a severe inflammatory disease characterized by cytokine storm, often accompanied by disseminated intravascular coagulation (DIC). PANoptosis is a novel form of cell death triggered by cytokine storms, characterized by a cascade reaction of pyroptosis, apoptosis, and necroptosis. It exists in septic platelets and is closely associated with the onset and progression of DIC. However, there remains an unmet need for drugs targeting PANoptosis. The anti-PANoptosis effect of myricetin was predicted using network pharmacology and confirmed through molecular docking. In vitro platelet activation models demonstrated that myricetin significantly attenuated platelet particle release, integrin activation, adhesion, spreading, clot retraction, and aggregation. Moreover, in a sepsis model, myricetin reduced inflammatory infiltration in lung tissue and platelet activation while improving DIC. Additionally, whole blood sequencing samples from sepsis patients and healthy individuals were analyzed to elucidate the up-regulation of the PANoptosis targets. Our findings demonstrate the inhibitory effect of myricetin on septic platelet PANoptosis, indicating its potential as a novel anti-cellular PANoptosis candidate and therapeutic agent for septic DIC. Furthermore, our study establishes a foundation for utilizing network pharmacology in the discovery of new drugs to treat various diseases.

MiR-141-3p-Functionalized Exosomes Loaded in Dissolvable Microneedle Arrays for Hypertrophic Scar Treatment.

Hypertrophic scar (HS) is a common fibroproliferative disease caused by abnormal wound healing after deep skin injury. However, the existing approaches have unsatisfactory therapeutic effects, which promote the exploration of newer and more effective strategies. MiRNA-modified functional exosomes delivered by dissolvable microneedle arrays (DMNAs) are expected to provide new hope for HS treatment. In this study, a miRNA, miR-141-3p, which is downregulated in skin scar tissues and in hypertrophic scar fibroblasts (HSFs), is identified. MiR-141-3p mimics inhibit the proliferation, migration, and myofibroblast transdifferentiation of HSFs in vitro by targeting TGF-ß2 to suppress the TGF-ß2/Smad pathway. Subsequently, the engineered exosomes encapsulating miR-141-3p (miR-141-3pOE -Exos) are isolated from adipose-derived mesenchymal stem cells transfected with Lv-miR-141-3p. MiR-141-3pOE -Exos show the same inhibitive effects as miR-141-3p mimics on the pathological behaviors of HSFs in vitro. The DMNAs for sustained release of miR-141-3pOE -Exos are further fabricated in vivo. MiR-141OE -Exos@DMNAs effectively decrease the thickness of HS and improve fibroblast distribution and collagen fiber arrangement, and downregulate the expression of α-SMA, COL-1, FN, TGF-ß2, and p-Smad2/3 in the HS tissue. Overall, a promising, effective, and convenient exosome@DMNA-based miRNA delivery strategy for HS treatment is provided.

Effect of physical activity intervention on weight change in rural older Chinese: a cluster randomized controlled trial.

BACKGROUND: Current randomized trial evidence for the effects of physical activity intervention on weight change in adults was mainly from western countries, with little reliable evidence from low- and middle-income countries, such as China, where lifestyle factors and obesity patterns differ substantially from those in western countries. We examined the effects of physical activity intervention on weight change using cluster randomized trial data among Chinese older adults. METHODS: The cluster randomized controlled trial included an 8-week physical activity intervention period and was followed up to 24 months. Eight villages were randomly assigned to the intervention group (4 villages, n = 240) or the control group (4 villages, n = 268). The intervention group received physical activity intervention based on the socio-ecological model, while the control group did not. The intervention involved three levels: individual, interpersonal, and community levels, which aimed to promote leisure-time physical activity of participants. The primary outcome of the present study was the difference in percentage weight change at 24 months from baseline. We used Tanita BC-601 analyzer scales to measure weight and recorded it to the nearest 0.1 kg. RESULTS: Among the 508 participants, the mean age was 70.93 (SD, 5.69) years, and 55.5% were female. There were significant differences in percentage weight change between the intervention group and the control group with a mean change of -1.78% (95% CI, -2.67% to -0.90%; p < 0.001) in the total sample, -1.94% (95% CI, -3.14% to -0.73%; p = 0.002) in participants with overweight/obesity, and -1.45% (95% CI, -2.73% to -0.18%; p = 0.027) among participants with underweight/healthy weight in favor of the intervention group at 24 months. CONCLUSIONS: Physical activity intervention resulted in weight loss in rural older sample at 24 months. This suggested that physical activity interventions are feasible for weight loss among older adults, especially for those with overweight/obesity or aged under 80. TRIAL REGISTRATION: The study has been registered on the Chinese Clinical Trial Registry on April 20, 2021 (ChiCTR2100045653), https://www.chictr.org.cn/showproj.html?proj=123704 .

PET imaging for the early evaluation of ocular inflammation in diabetic rats by using [18F]-DPA-714.

Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([18F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [18F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [18F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [18F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM.

Correction of Lying Ear and Aesthetic Modification of Helix and Ear Lobule With Hyaluronic Acid Filler Injection: Experience in Chinese Patients.

BACKGROUND: Large and long ears are regarded as symbols of wealth and health in East Asian culture, and people with lying ears often want their ears to be more exposed and prominent. Surgeries to correct lying ears have been documented. OBJECTIVES: The aim of this study was to report the correction of lying ears and the aesthetic modification of helix and ear lobule with hyaluronic acid (HA) injections. METHODS: HA injections were performed at the auriculocephalic sulcus to increase the cranioauricular angle (CA) and correct lying ears. The injections at helix and lobule were case specific. The CA was measured and photographs were taken at baseline and at 1-, 3-, 6-, and 10-month follow-ups. Efficacy was assessed with the 5-point Global Aesthetic Improvement Scale (GAIS). Adverse events were recorded. RESULTS: Forty-six patients (92 ears) received HA injections and completed follow-ups. Instant correction outcomes were observed. Sixteen (34.8%) patients received 1 touch-up injection, the clinical efficacy of which persisted for 1 to 1.5 years. For over 90% of cases with touch-up treatment the GAIS was "very much improved" or "much improved" at all follow-ups. The GAIS for over 70% of cases without touch-up treatment was "very much improved" or "much improved" at 1-, 3-, and 6-month follow-ups. CA increased significantly compared with the baseline. Patients also reported "more V-shaped face shape" and "lifted jawline" effects. No serious adverse events occurred. CONCLUSIONS: As an alternative technique to surgeries, HA filler injections at the auriculocephalic sulcus effectively corrected lying ears. This technique produced immediate, long-lasting, and aesthetically pleasing results. The side effects and downtime were minimal.

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Cholelithiasis is a common disease of the digestive system. The risk factors for cholelithiasis have been reported and summarized many times in the published literature, which primarily focused on cross-sectional studies. Due to the inherent limitations of the study design, the reported findings still need to be validated in additional longitudinal studies. Moreover, a number of new risk factors for cholelithiasis have been identified in recent years, such as bariatric surgery, hepatitis B virus infection, hepatitis C virus infection, kidney stones, colectomy, osteoporosis, etc. These new findings have not yet been included in published reviews. Herein, we reviewed the 101 cholelithiasis-associated risk factors identified through research based on longitudinal investigations, including cohort studies, randomized controlled trials, and nested case control studies. The risk factors associated with the pathogenesis of cholelithiasis were categorized as unmodifiable and modifiable factors. The unmodifiable factors consist of age, sex, race, and family history, while the modifiable factors include 37 biological environmental factors, 25 socioenvironmental factors, and 35 physiochemical environmental factors. This study provides thorough and comprehensive ideas for research concerning the pathogenesis of cholelithiasis, supplying the basis for identifying high-risk groups and formulating relevant prevention strategies.

Supramolecular Polymer Frameworks with Controlled and Uniform Pore Apertures.

Porous frameworks with controlled pore structure and tunable aperture are greatly demanded. However, precise synthesis of this kind of materials is a formidable challenge. Herein, we report the fabrication of two-dimensional (2D) supramolecular polymer frameworks using a precisely synthesized rod-like helical polyisocyanide as link. Four three-arm star-shaped polyisocyanides with the degree of the polymerization of 10, 20, 30 and 40, and having 2-ureido-4[1H]-pyrimidinone (UPy) terminals were synthesized. 2D-Crystalline polymer frameworks with apertures of 5.3, 10.1, 13.9, and 19.1 nm were respectively obtained through intermolecular hydrogen bonding interaction between the terminal Upy units. The pore aperture is dependent on the length of polyisocyanide backbone. Thus, well-defined supramolecular polymer frameworks with controlled and uniform hexagonal pores were obtained, as proved by small-angle X-ray scattering (synchrotron radiation facility), atomic force microscopy, and Brunauer-Emmett-Teller analyses. The frameworks with uniform large pore aperture were used to purify nanomaterials and immobilize biomacromolecules. For instance, the membranes of the polymer frameworks could size-fractionation of silver nanoparticles into uniform nanoparticles with very low dispersity. The frameworks with large aperture facilitated the inclusion of myoglobin and enhanced the stability and catalytic activity.

Oxytocin and the Punitive Hub-Dynamic Spread of Cooperation in Human Social Networks.

Human society operates on large-scale cooperation. However, individual differences in cooperativeness and incentives to free ride on others' cooperation make large-scale cooperation fragile and can lead to reduced social welfare. Thus, how individual cooperation spreads through human social networks remains puzzling from ecological, evolutionary, and societal perspectives. Here, we identify oxytocin and costly punishment as biobehavioral mechanisms that facilitate the propagation of cooperation in social networks. In three laboratory experiments (n = 870 human participants: 373 males, 497 females), individuals were embedded in heterogeneous networks and made repeated decisions with feedback in games of trust (n = 342), ultimatum bargaining (n = 324), and prisoner's dilemma with punishment (n = 204). In each heterogeneous network, individuals at central positions (hub nodes) were given intranasal oxytocin (or placebo). Giving oxytocin (vs matching placebo) to central individuals increased their trust and enforcement of cooperation norms. Oxytocin-enhanced norm enforcement, but not elevated trust, explained the spreading of cooperation throughout the social network. Moreover, grounded in evolutionary game theory, we simulated computer agents that interacted in heterogeneous networks with central nodes varying in terms of cooperation and punishment levels. Simulation results confirmed that central cooperators' willingness to punish noncooperation allowed the permeation of the network and enabled the evolution of network cooperation. These results identify an oxytocin-initiated proximate mechanism explaining how individual cooperation facilitates network-wide cooperation in human society and shed light on the widespread phenomenon of heterogeneous composition and enforcement systems at all levels of life.SIGNIFICANCE STATEMENT Human society operates on large-scale cooperation. Yet because cooperation is exploitable by free riding, how cooperation in social networks emerges remains puzzling from evolutionary and societal perspectives. Here we identify oxytocin and altruistic punishment as key factors facilitating the propagation of cooperation in human social networks. Individuals played repeated economic games in heterogeneous networks where individuals at central positions were given oxytocin or placebo. Oxytocin-enhanced cooperative norm enforcement, but not elevated trust, explained cooperation spreading throughout the social network. Evolutionary simulations confirmed that central cooperators' willingness to punish noncooperation allowed the permeation of the network and enabled the evolution of cooperation. These results identify an oxytocin-initiated proximate mechanism explaining how individual cooperation facilitates network-wide cooperation in human social networks.

Cyclic Polymers: Controlled Synthesis, Properties and Perspectives.

Recently, cyclic polymers have attracted increasing interest due to their unique topologies, properties, and functions compared to the linear analogues. This mini-review focuses on the recent advances in the synthesis and applications of cyclic polymers. First, the main synthetic methods for cyclic polymers, namely ring closure and ring expansion methods, are presented and discussed, followed by a review on the exploration of the properties and applications of synthetic cyclic polymers. Finally, a critical assessment of the preliminary studies exploring the efficient synthesis and potential applications of cyclic polymers are presented, and the remaining challenges in the field as well as ideas for solving these challenges will be discussed.

Not all Rectal Cancer Patients Could Benefit From the Surgery on the Primary Site.

AIM: Previous studies have provided evidence that primary site surgery can improve the prognosis of rectal cancer patients, even in those with advanced age and distant metastasis, though results have been inconsistent. The current study aims to determine if all rectal cancer patients are likely to benefit from surgery in terms of overall survival. METHODS: This study examined the impact of primary site surgery on the prognosis of rectal cancer patients diagnosed between 2010 and 2019 using multivariable Cox regression analysis. The study also stratified patients by age group, M stage, chemotherapy, radiotherapy, and number of distant metastatic organs. The propensity score matching method was used to balance observed covariates between patients who received and did not receive surgery. The Kaplan-Meier method was used to analyze the data, and the log-rank test was used to determine differences between patients who did and did not undergo surgery. RESULTS: The study included 76,941 rectal cancer patients, with a median survival of 81.0 months (95% CI: 79.2-82.8 months). Of these patients, 52,360 (68.1%) received primary site surgery, and they tended to be younger, have higher differentiated grade, earlier T, N, M stage, and lower rates of bone, brain, lung, and liver metastasis, chemotherapy, and radiotherapy than those without surgery. Multivariable Cox regression analysis revealed that surgery had a protective effect on the prognosis of rectal cancer patients, including those with advanced age, distant metastasis, and multiple organ metastasis, but not in patients with four organ metastases. The results were also confirmed using propensity score matching. CONCLUSION: Not all rectal cancer patients could benefit from the surgery on the primary site, especially the patients with more than four distant metastases. The results could help the clinicians to tailor targeted treatment regimens and provide a guideline for making surgical decisions.

First-principles prediction of the thermal conductivity of two configurations of difluorinated graphene monolayer.

Lattice thermal conductivity (κL) plays a crucial role in the thermal management of electronic devices. In this study, we systematically investigate the thermal transport properties of monolayer fluorinated graphene using a combination of machine learning-based interatomic potentials and the phonon Boltzmann transport equation. At a temperature of 300 K, we find that the κL values for chair-configured fluorinated graphene monolayers are 184.24 W m-1 K-1 in the zigzag direction and 205.57 W m-1 K-1 in the armchair direction. For the boat configuration, the κL values are 120.45 W m-1 K-1 and 64.26 W m-1 K-1 in the respective directions. The disparities in κL between these two configurations predominantly stem from differences in phonon relaxation times, which can be elucidated by examining the Grüneisen parameters representing the degree of anharmonicity. A more in-depth analysis of bond strengths, as assessed by the crystal orbital Hamiltonian population, reveals that the stronger in-plane CC bonds in chair-configured fluorinated graphene monolayers are the primary contributors to the observed variations in anharmonicity.

Anti-glioma effect of ginseng-derived exosomes-like nanoparticles by active blood-brain-barrier penetration and tumor microenvironment modulation.

Inhibition of tumor growth and normalization of immune responses in the tumor microenvironment (TME) are critical issues for improving cancer therapy. However, in the treatment of glioma, effective nanomedicine has limited access to the brain because of the blood-brain barrier (BBB). Previously, we demonstrated nano-sized ginseng-derived exosome-like nanoparticles (GENs) consisting of phospholipids including various bioactive components, and evaluated anti-tumor immune responses in T cells and Tregs to inhibit tumor progression. It was found that the enhanced targeting ability of GENs to the BBB and glioma induced a significant therapeutic effect and exhibited strong efficacy in recruiting M1 macrophage expression in the TME. GENs were demonstrated to be successful candidates in glioma therapeutics both in vitro and in vivo, suggesting excellent potential for inhibiting glioma progression and regulating tumor-associated macrophages (TAMs).

Panax notoginseng: derived exosome-like nanoparticles attenuate ischemia reperfusion injury via altering microglia polarization.

Cerebral ischemia/reperfusion (CI/R) injury is a clinical conundrum during the treatment of ischemic stroke. Cell-derived exosomes (CDE) were proved to be therapeutically effective for CI/R injury. However, production of CDE is time and effort consuming. Increasing studies reported that plants can also generate exosome-like nanoparticles (ELN) which are therapeutically effective and have higher yield compared with CDE. In this study, a commonly used Chinese herb Panax notoginseng (PN), whose active ingredients were well-documented in the treatment of CI/R injury, was chosen as a source of ELNs. It was found that Panax notoginseng derived exosome like nanoparticles (PDN) could enter the brain without modification and ameliorate cerebral infarct volume, improve behavior outcome and maintained the integrity of BBB. PDNs attenuated CI/R injury by altering the phenotype of microglia from "pro-inflammation" M1 type to "anti-inflammation" M2 type. Also, we found that lipids from PDNs were the major therapeutic effective component. As a mechanism of action, PDN was proved to exert therapeutic effect via activating pI3k/Akt pathway.

Characterization and phylogenetic analysis of the complete mitochondrial genome of Rhabdias kafunata (Rhabditida: Rhabdiasidae).

Rhabdias kafunata (Rhabditida: Rhabdiasidae) is a parasitic nematode that significantly affects bufonids. To better understand the genome-level characteristics of related species, Illumina sequencing was used to identify mitochondrial genes and analyze their basic characteristics and gene arrangements. The mitogenome of R. kafunata is 14,068 bp in length and contains 36 genes, including 12 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes and one noncoding region (NCR). The nucleotide composition is highly biased toward A + T, accounting for 75.5% of the entire mitochondrial genome. The cox1 sequence is relatively conserved in Ka/Ks analyses and can be used as a gene fragment for species identification. While 8 of the 12 PCGs use the typical ATN initiation codon, nad1-2, nad4, and cox3 utilize a TTG initiation codon. Most stop codons end with the standard TAA or TAG, except for cytb, which ends with an incomplete TA. Additionally, trnM, trnK, and trnI have the typical clover-leaf secondary structure, while the remaining tRNAs lack the DHU arm or TΨC arm. Phylogenetic analysis indicates that R. kafunata belongs to the Rhabditidae family and is closely related to Litoditis marina and Caenorhabditis angaria among sequenced lepidopteran mitochondrial genomes.

NINJ1 Regulates Platelet Activation and PANoptosis in Septic Disseminated Intravascular Coagulation.

Disseminated intravascular coagulation (DIC), which is closely related to platelet activation, is a key factor leading to high mortality in sepsis. The release of contents from plasma membrane rupture after platelet death further aggravates thrombosis. Nerve injury-induced protein 1 (NINJ1) is a cell membrane protein that mediates membrane disruption, a typical marker of cell death, through oligomerization. Nevertheless, whether NINJ1 is expressed in platelets and regulates the platelet function remains unclear. The aim of this study was to evaluate the expression of NINJ1 in human and murine platelets and elucidate the role of NINJ1 in platelets and septic DIC. In this study, NINJ1 blocking peptide (NINJ126-37) was used to verify the effect of NINJ1 on platelets in vitro and in vivo. Platelet αIIbß3 and P-selectin were detected by flow cytometry. Platelet aggregation was measured by turbidimetry. Platelet adhesion, spreading and NINJ1 oligomerization were examined by immunofluorescence. Cecal perforation-induced sepsis and FeCl3-induced thrombosis models were used to evaluate the role of NINJ1 in platelet, thrombus and DIC in vivo. We found that inhibition of NINJ1 alleviates platelet activation in vitro. The oligomerization of NINJ1 is verified in membrane-broken platelets, which is regulated by the PANoptosis pathway. In vivo studies demonstrate that inhibition of NINJ1 effectively reduces platelet activation and membrane disruption, thus suppressing platelet-cascade reaction and leading to anti-thrombosis and anti-DIC in sepsis. These data demonstrate that NINJ1 is critical in platelet activation and plasma membrane disruption, and inhibition of NINJ1 effectively reduces platelet-dependent thrombosis and DIC in sepsis. This is the first study to reveal the key role of NINJ1 in platelet and its related disorders.