Oligodendrocyte precursor cells ingest axons in the mouse neocortex.

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmission electron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.

Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer.

Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored host-microbiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1-CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga. Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella, contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets.NEW & NOTEWORTHY This study determined the following: 1) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME.

NAFLDkb: A Knowledge Base and Platform for Drug Development against Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with a broad spectrum of histologic manifestations. The rapidly growing prevalence and the complex pathologic mechanisms of NAFLD pose great challenges for treatment development. Despite tremendous efforts devoted to drug development, there are no FDA-approved medicines yet. Here, we present NAFLDkb, a specialized knowledge base and platform for computer-aided drug design against NAFLD. With multiperspective information curated from diverse source materials and public databases, NAFLDkb presents the associations of drug-related entities as individual knowledge graphs. Practical drug discovery tools that facilitate the utilization and expansion of NAFLDkb have also been implemented in the web interface, including chemical structure search, drug-likeness screening, knowledge-based repositioning, and research article annotation. Moreover, case studies of a knowledge graph repositioning model and a generative neural network model are presented herein, where three repositioning drug candidates and 137 novel lead-like compounds were newly established as NAFLD pharmacotherapy options reusing data records and machine learning tools in NAFLDkb, suggesting its clinical reliability and great potential in identifying novel drug-disease associations of NAFLD and generating new insights to accelerate NAFLD drug development. NAFLDkb is freely accessible at https://www.biosino.org/nafldkb and will be updated periodically with the latest findings.

How different face mask types affect interpersonal distance perception and threat feeling in social interaction.

Due to the easing of the pandemic, public policies no longer mandated people to wear masks. People can choose to no wear or wear different types of masks based on personal preferences and safety perceptions during daily interaction. Available information about the influence of face mask type on interpersonal distance (IPD) by different aging populations is still lacking. Thus, this study aimed to investigate the face mask type (no wear, cloth, medical and N95 mask) and age group effect of avatars (children, adults and older adults) on IPD perception, threat feeling and physiological skin conductance response under active and passive approaching. One hundred participants with a range from 20 to 35 years old were recruited for this study. Twelve avatars (three age groups*four face mask conditions) were created and applied in a virtual reality environment. The results showed that age group, mask type and approach mode had significant effects on IPD and subjective threat feeling. A non-significant effect was found on skin conductance responses. Participants maintained a significantly longer IPD when facing the older adults, followed by adults and then children. In the passive approach condition, people tended to maintain a significantly greater comfort distance than during the active approach. For the mask type effect, people kept a significantly largest and shortest IPD when facing an avatar with no mask or the N95 mask, respectively. A non-significant IPD difference was found between the N95 and medical mask. Additionally, based on the subjective threat feeling, facing an avatar wearing a medical mask generated the lowest threat feeling compared to the others. The findings of this study indicated that wearing medical masks provided a benefit in bringing people closer for interaction during specific situations. Understanding that mask-wearing, especially medical one, brought to shortest IPD when compared to the unmasked condition can be utilized to enhance safety measures in crowded public spaces and health-care settings. This information could guide the development of physical distancing recommendations, taking into account both the type of mask and the age groups involved, to ensure the maintenance of appropriate distances.

Efficacy of Ice Compress Combined With Serratus Anterior Plane Block in Analgesia After Thoracoscopic Pneumonectomy: A Randomized Controlled Study.

PURPOSE: To explore the analgesic effect of the ice pack combined with serratus anterior plane block after thoracoscopic pulmonary resection. DESIGN: A randomized controlled trial design. METHODS: This prospective randomized controlled trial recruited patients who underwent thoracoscopic pneumonectomy in a grade A tertiary hospital from October 2021 to March 2022. The patients were randomly divided into the control group, the serratus anterior plane block group, the ice pack group, and the ice pack combined with serratus anterior plane block group. The analgesic effect was evaluated by collecting the postoperative visual analog score. FINDINGS: A total of 133 patients agreed to participate in this study, of which 120 patients were eventually included (n = 30/group). The primary outcome was that the pain in SAP block group, ice pack group, and ice pack combined with SAP block group decreased significantly within 24 hours compared with the control group (P < .05). Also, significant differences were noted in other secondary outcomes, such as Prince-Henry pain score within 12 hours, 15-item quality of recovery (QoR-15) score within 24 hours, and fever times within 24 hours. No significant difference was detected in the C-reactive protein value, white blood cell count, and the use of additional analgesics within 24 hours postoperatively (P > .05). CONCLUSIONS: For patients after thoracoscopic pneumonectomy, ice pack, serratus anterior plane block, and ice pack combined with serratus anterior plane block produce better postoperative analgesic effects than intravenous analgesia. The combined group exhibited the best outcomes.

l-Asparaginase synergizes with etoposide via the PI3K/Akt/mTOR pathway in Epstein-Barr virus-positive Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive Epstein-Barr virus (EBV)-driven B-cell lymphoma characterized by the translocation and rearrangement of the c-Myc proto-oncogene. High-intensity multidrug chemotherapy regimens have a limited effect on the survival of refractory or relapsed BL patients, mainly owing to the high EBV load and drug resistance. l-asparaginase ( l-Asp) and etoposide (VP-16) play a beneficial role in EBV-related lymphoproliferative diseases; however, their roles and mechanisms in BL remain unclear. In this study, we found that VP-16 inhibited BL cell proliferation and arrested the cell cycle at the G2 /M phase. It also induced autophagy and activated the extrinsic and intrinsic apoptotic signaling pathways in BL cells. Mechanistically, VP-16 inhibited c-Myc expression and regulated the PI3K/Akt/mTOR signaling pathway. Notably, VP-16 also showed a specific synergistic effect with l-Asp to induce apoptosis in EBV-positive BL cells but not in EBV-negative BL cells. VP-16 combined with l-Asp further inhibited c-Myc expression and downregulated the PI3K/Akt/mTOR signaling pathway. Additionally, we found that VP-16 inhibited the expression of latent membrane protein 1 (LMP1), and in combination with l-Asp further decreased LMP1 expression in Raji cells. Our in vivo data also showed that the dual-drug combination significantly inhibited the growth of BL tumors and prolonged the survival of mice compared to VP-16 alone. In conclusion, this study provides new evidence that l-Asp may enhance the antitumor effect of VP-16 by inhibiting the PI3K/Akt/mTOR signaling pathway in EBV-positive BL cells.

Mallotucin D, a Clerodane Diterpenoid from Croton crassifolius, Suppresses HepG2 Cell Growth via Inducing Autophagic Cell Death and Pyroptosis.

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from Croton crassifolius, has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.

Bayesian penalized Buckley-James method for high dimensional bivariate censored regression models.

For high dimensional gene expression data, one important goal is to identify a small number of genes that are associated with progression of the disease or survival of the patients. In this paper, we consider the problem of variable selection for multivariate survival data. We propose an estimation procedure for high dimensional accelerated failure time (AFT) models with bivariate censored data. The method extends the Buckley-James method by minimizing a penalized [Formula: see text] loss function with a penalty function induced from a bivariate spike-and-slab prior specification. In the proposed algorithm, censored observations are imputed using the Kaplan-Meier estimator, which avoids a parametric assumption on the error terms. Our empirical studies demonstrate that the proposed method provides better performance compared to the alternative procedures designed for univariate survival data regardless of whether the true events are correlated or not, and conceptualizes a formal way of handling bivariate survival data for AFT models. Findings from the analysis of a myeloma clinical trial using the proposed method are also presented.

Bilateral triceps tendon approach is flexible and efficient in the treatment of type C distal humerus fractures.

PURPOSE: The purpose of this study was to assess and compare elbow range of motion, triceps extension strength and functional results of type C (AO/OTA) distal humerus fractures treated with bilateral triceps tendon (BTT) approach and olecranon osteotomy (OO). At the same time, we are also trying to know whether BTT approach can provide sufficient vision for comminuted intra-articular fractures of the distal humerus, and whether it is convenient to convert to the treatment to total elbow arthroplasty (TEA) or OO. METHODS: Patients treated with OO and BTT approaches for type C distal humerus fractures between July 2014 and December 2017 were retrospectively reviewed. Inclusion criteria include: (1) patients' age were more than 18 years old, (2) follow-up was no less than 6 months, and (3) patients were diagnosed with type C fractures (based on the AO/OTA classification). Exclusion criteria include: (1) open fractures (Gustillo type 2 or type 3), (2) treated by other approaches, and (3) presented with combined injuries of ipsilateral upper extremities, such as ulnar nerve. Elbow range of motion and triceps extension strength testing were completely valuated, when the fractures had healed. Assessment of functional results using the Mayo elbow performance score and complications were conducted in final follow-up. The data were compared using the two tailed Student's t-test. All data were presented as mean ± standard deviation. RESULTS: Eighty-six patients of type C distal humerus fractures, treated by OO and BTT approach were retrospectively reviewed between July 2014 and December 2017. Fifty-five distal humerus fractures (23 males and 32 females, mean age 52.7 years) treated by BTT approach or OO were included in this study. There were 10 fractures of type C1, 16 type C2 and 29 type C3 according to the AO/OTA classification. Patients were divided into two surgical approach groups chosen by the operators: BTT group (28 patients) and OO group (27 patients). And the mean follow-up time of all patients was 15.6 months (range, 6-36 months). Three cases in BTT group were converted to TEA, and one converted to OO. Only one case in BTT group presented poor articular reduction with a step more than 2 mm. There were not significantly different in functional outcomes according to the Mayo elbow performance score, operation time and extension flexion motion are values between BTT group and OO group (p > 0.05). Complications and reoperation rate were also similar in the two groups. Triceps manual muscle testing were no significant difference in the two groups, even subdivided in elder patients (aged >60 years old). CONCLUSION: BTT is a safe approach to achieve similar functional result comparing with OO. BTT were not suitable for every case with severe comminuted pattern, but it avoids the potential complications related to OO, and has no complications concerning with triceps tendon. It is convenient for open reduction internal fixation and flexible to be converted to OO, as well as available to be converted to TEA in elder patients.

Advantages of pure platelet-rich plasma compared with leukocyte- and platelet-rich plasma in promoting repair of bone defects.

BACKGROUND: High levels of pro-inflammatory cytokines in leukocyte- and platelet-rich plasma (L-PRP) may activate the nuclear factor κB (NF-κB) pathway to counter the beneficial effect of the growth factors on bone regeneration. However, to date, no relevant studies have substantiated this. METHODS: L-PRP and pure platelet-rich plasma (P-PRP) were isolated. The in vitro effects of L-PRP and P-PRP on the proliferation, viability and migration of human bone marrow-derived mesenchymal stem cells (HBMSCs) and EaHy926, tube formation of EaHy926, and osteogenic differentiation of HBMSCs were assessed by cell counting, flow cytometry, scratch assay, tube formation assay, and real-time quantitative polymerase chain reaction (RT-PCR), western blotting and Alizarin red staining, respectively. The in vitro effects of L-PRP and P-PRP on the nuclear translocation of NF-κB p65, mRNA expression of inducible nitric oxide synthase and cyclooxygenase-2, and production of prostaglandin E2 and nitric oxid were assessed by western blotting, RT-PCR, enzyme-linked immunosorbent assay and Griess reaction, respectively. The in vivo effects of L-PRP or P-PRP preprocessed ß-tricalcium phosphate (ß-TCP) on the calvarial defects in rats were assessed by histological and immunofluorescence examinations. RESULTS: P-PRP, which had similar platelet and growth factors concentrations but significantly lower concentrations of leukocytes and pro-inflammatory cytokines compared with L-PRP, promoted the proliferation, viability and migration of HBMSCs and EaHy926, tube formation of EaHy926 and osteogenic differentiation of HBMSCs in vitro, compared with L-PRP. The implantation of P-PRP preprocessed ß-TCP also yielded better histological results than the implantation of L-PRP preprocessed ß-TCP in vivo. Moreover, L-PRP treatment resulted in the activation of the NF-κB pathway in HBMSCs and EaHy926 in vitro while the postoperative delivery of caffeic acid phenethyl ester, an inhibitor of NF-κB activation, enhanced the histological results of the implantation of L-PRP preprocessed ß-TCP in vivo. CONCLUSIONS: Leukocytes in L-PRP may activate the NF-κB pathway via the increased pro-inflammatory cytokines to induce the inferior effects on bone regeneration of L-PRP compared with P-PRP. Hence, P-PRP may be more suitable for bone regeneration compared with L-PRP, and the combined use of P-PRP and ß-TCP represents a safe, simple, and effective alternative option for autogenous bone graft in the treatment of bone defects.