Astrocytes are the largest glial population in the mammalian brain. However, we have a minimal understanding of astrocyte development, especially fate specification in different regions of the brain. Through lineage tracing of the progenitors of the third ventricle (3V) wall via in-utero electroporation in the embryonic mouse brain, we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall. Unexpectedly, radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types: radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon. With genetic fate mapping analysis, we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon. Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon. With transcriptomic analysis of the region-specific 3V wall and lateral ventricle (LV) wall, we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon. Together, these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.
Mice ; Animals ; Astrocytes ; Neuroglia/physiology* ; Diencephalon ; Brain ; Neurons ; Mammals

After entering the body from the drug delivery site, antitumor nanomedicines need to cross a series of physiopathological barriers to reach the target site of action to effectively exert antitumor therapeutic effects. The ligand modification strategy is a classic method to enhance the efficiency of nanomedicine delivery in vivo, but the contradiction between the single ligand modification strategy, which is characterized by unity and stage, and the in vivo delivery process, which is characterized by versatility and whole-process characteristics, determines that nanomedicines modified by a single ligand alone cannot satisfy the target efficacy requirements. Therefore, the use of multiligand combinatorial modification strategies by virtue of nanomedicine surface area advantages is key to advancing the next generation of smart nanomedicines. In this paper, on the basis of summarizing and classifying the commonly used functional ligands for in vivo delivery, the advantages and research progress of multiligand combination modification of antitumor nanomedicines are discussed with special focus, and the multiligand combination modification is classified as synergistic and complementary according to the combination of the ligands, which is of great significance to ensure that antitumor nanomedicines can overcome the multiple physiopathological barriers to achieve precise delivery.

Objective To construct curcumin pyrazole derivative by the reaction of diketone of curcumin and benzylhydrazine based on the above structure-activity relationship,and to explore its antioxidant activity to provide experimental basis for the development of curcumin antioxidant derivative.Methods Curcumin-N-substituted pyrazole derivative was synthesized from curcumin and benzylhydrazine.The structures of the derivative were confirmed by infrared spectroscopy(IR),nuclear magnetic resonance spectroscopy(1H-NMR,13C-NMR)and LC-MS.The antioxidant activity in vitro of the derivative was evaluated by determination of curcumin and its pyrazole derivative scavenging ability for 2,2-diphenyl-1-picrylhydrazyl(DPPH)free radical and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid(ABTS)free radical.Results Curcumin pyrazole derivative was successfully synthesized.Curcumin and its pyrazole derivative showed good free radical scavenging effects in the range of 4.6-73.6,6.25-100 μg·mL-1,respectively,with a significant dose-effect relationship.The half-maximal inhibition(IC50)values of curcumin and its pyrazole derivatives determined by DPPH method were 14.24,40.37 μg·mL-1,respectively,while the IC50 values of curcumin and its pyrazole derivatives determined by ABTS method were 36.65,19.26 μg·mL-1,respectively.Conclusion The antioxidant activity of β-dione of curcumin was retained through the substitution of the pyrazole ring,and the curcumin pyrazole derivative deserves further investigation as a potential antioxidant.

Objective To establish a dynamic prediction model of fatal massive hemorrhage in trauma based on the vital signs time series data and machine learning algorithms.Methods Retrospectively analyze the vital signs time series data of 7522 patients with trauma in the Medical Information Mart for Intensive Care-Ⅳ(MIMIC-Ⅳ)database from 2008 to 2019.According to the occurrence of posttraumatic fatal massive hemorrhage,the patients were divided into two groups:fatal massive hemorrhage group(n=283)and non-fatal massive hemorrhage group(n=7239).Six machine learning algorithms,including logistic regression(LR),support vector machine(SVM),random forests(RF),adaptive boosting(AdaBoost),gated recurrent unit(GRU),and GRU-D were used to develop a dynamic prediction models of fatal massive hemorrhage in trauma.The probability of fatal massive hemorrhage in the following 1,2,and 3 h was dynamically predicted.The performance of the models was evaluated by accuracy,sensitivity,specificity,positive predictive value,negative predictive value,Youden index,and area under receiver operating characteristic curve(AUC).The models were externally validated based on the trauma database of the Chinese PLA General Hospital.Results In the MIMIC-Ⅳ database,the set of dynamic prediction models based on the GRU-D algorithm was the best.The AUC for predicting fatal major bleeding in the next 1,2,and 3 h were 0.946±0.029,0.940±0.032,and 0.943±0.034,respectively,and there was no significant difference(P=0.905).In the trauma dataset,GRU-D model achieved the best external validation effect.The AUC for predicting fatal major bleeding in the next 1,2,and 3 h were 0.779±0.013,0.780±0.008,and 0.778±0.009,respectively,and there was no significant difference(P=0.181).This set of models was deployed in a public web calculator and hospital emergency department information system,which is convenient for the public and medical staff to use and validate the model.Conclusion A set of dynamic prediction models has been successfully developed and validated,which is greatly significant for the early diagnosis and dynamic prediction of fatal massive hemorrhage in trauma.

Objective To analyze risk factors and pathogenic characteristics of intestinal colonization of carbape-nem-resistant Enterobacterales(CRE)in patients from intensive care unit(ICU).Methods A total of 392 ICU pa-tients who underwent intestinal CRE screening in a tertiary hospital in Changzhou from March to December,2023 were divided into the colonization group(n=42)and the non-colonization group(n=350)according to the screening results.Clinical data of patients,including age,gender,underlying diseases,malignant tumors,radiotherapy,chemotherapy,infection before the last screening,antimicrobial use,and invasive procedures were collected for the analysis on risk factors and pathogenicity.Results Among 42 patients with positive CRE screening results,44 CRE strains were detected,mainly Klebsiella pneumoniae(65.91％),followed by Escherichia coli(15.91％)and En-terobacter cloacae(13.64％).The average time from admission in ICU to positive screening results of intestinal CRE in the colonization group was 14 days.Long term use of carbapenem antibiotics(OR=1.47,95％CI:1.31-1.65),mechanical ventilation(OR=1.14,95％CI:1.06-1.22),and Enterobacterales infection(OR=10.10,95％CI:3.28-32.09)were independent risk factors for intestinal CRE colonization.Patients who received carbap-enem antibiotics for ≥15 days(x2=167.52,P＜0.001)and those who received mechanical ventilation for ≥15 days(x2=101.03,P＜0.001)had higher risks for intestinal CRE colonization.Conclusion In clinical practice,it is necessary to improve pathogen detection,treat Enterobacterales infection timely,choose carbapenem antibiotics carefully,shorten treatment course,actively evaluate indications for mechanical ventilation,and wean off ventilator timely.

Aim To investigate the intracellular up-take and target protein binding characteristics of two Bruton's tyrosine kinase inhibitors(BTKi)with differ-ent selectivities to provide further insights into the mechanisms of drug off-target-related bleeding risk.Methods Ibrutinib(non-selective BTKi)and za-nubrutinib(selective BTKi)were used as study drugs.After incubation of MEC-1 cells and human platelets with drugs,the cellular thermal shift assay(CETSA)was combined with Western blot to obtain the melting curve and isothermal curve to analyze the binding char-acteristics of the two drugs with the target protein BTK.After incubation of MEC-1 cells and human platelets with drugs,the concentrations of the two drugs were detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS)to analyze the intracellular uptake of the two drugs.Results CETSA analysis confirmed that zanubrutinib was more selective for the target protein BTK compared to ibrutinib.LC-MS/MS analysis showed that both drugs were uptaken intracel-lularly by MEC-1 cells and platelets in a concentration-dependent manner.Conclusions While BTKi targe-ting BTK to B lymphocytes exerts therapeutic effects,off-target effects on platelets due to differences in their intracellular uptake,and target-binding characteristics may be one of the reasons for the differences in bleed-ing risk across selective BTKi.

Purpose::Internal iliac artery ligation (IIAL) has been used as a damage control procedure to treat hemodynamically unstable pelvic fracture for many years. However, there is ongoing debate regarding the effectiveness and safety of this hemostatic method. Therefore, we performed a systematic literature review to assess the efficacy and safety of IIAL for pelvic fracture hemostasis.Methods::Three major databases, PubMed, Embase, and Google Scholar, were searched to screen eligible original studies published in English journals. Two reviewers independently read the titles, abstracts, and full texts of all literature. Articles were included if they reported the use and effects of IIAL.Results::A total of 171 articles were initially identified, with 22 fully meeting the inclusion criteria. Among the analyzed cases, up to 66.7% of patients had associated abdominal and pelvic organ injuries, with the urethra being the most frequently injured organ, followed by the bowel. The outcomes of IIAL for achieving hemostasis in pelvic fractures were found to be satisfactory, with an effective rate of 80%. Hemorrhagic shock was the leading cause of death, followed by craniocerebral injury. Notably, no reports of ischemic complications involving the pelvic organs due to IIAL were found.Conclusion::IIAL has a good effect in treating hemodynamically unstable pelvic fracture without the risk of pelvic organ ischemia. This procedure should be considered a priority for hemodynamically unstable pelvic fracture patients with abdominal organ injuries.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Both anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are common causes of pulmonary-renal syndrome. Organizing pneumonia (OP), a special pattern of interstitial lung disease, is extremely rare either in AAV or anti-GBM disease. We report an old woman presented with OP on a background of co-presentation with both ANCA and anti-GBM antibodies.
Female ; Humans ; Antibodies, Antineutrophil Cytoplasmic ; Organizing Pneumonia ; Autoantibodies ; Glomerulonephritis ; Anti-Glomerular Basement Membrane Disease ; Pneumonia ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications*

This study aimed to explore the mechanism of Cistanches Herba in the treatment of cancer-induced fatigue(CRF) by network pharmacology combined with in vivo and in vitro experiments to provide a theoretical basis for the clinical medication. The chemical constituents and targets of Cistanches Herba were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The targets of CRF were screened out by GeneCards and NCBI. The common targets of traditional Chinese medicine and disease were selected to construct a protein-protein interaction(PPI) network, followed by Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. A visual signal pathway rela-ted to Chinese medicine and disease targets was constructed. The CRF model was induced by paclitaxel(PTX) in mice. Mice were divided into a control group, a PTX model group, and low-and high-dose Cistanches Herba extract groups(250 and 500 mg·kg~(-1)). The anti-CRF effect in mice was evaluated by open field test, tail suspension test, and exhaustive swimming time, and the pathological morphology of skeletal muscle was evaluated by hematoxylin-eosin(HE) staining. The cancer cachexia model in C2C12 muscle cells was induced by C26 co-culture, and the cells were divided into a control group, a conditioned medium model group, and low-, medium-, and high-dose Cistanches Herba extract groups(62.5, 125, and 250 μg·mL~(-1)). The reactive oxygen species(ROS) content in each group was detected by flow cytometry, and the intracellular mitochondrial status was evaluated by transmission electron microscopy. The protein expression levels of hypoxia-inducible factor-1α(HIF-1α), BNIP3L, and Beclin-1 were detected by Western blot. Six effective constituents were screened out from Cistanches Herba. The core genes of Cistanches Herba in treating CRF were AKT1, IL-6, VEGFA, CASP3, JUN, EGFR, MYC, EGF, MAPK1, PTGS2, MMP9, IL-1B, FOS, and IL10, and the pathways related to CRF were AGE-RAGE and HIF-1α. Through GO enrichment analysis, it was found that the main biological functions involved were lipid peroxidation, nutrient deficiency, chemical stress, oxidative stress, oxygen content, and other biological processes. The results of the in vivo experiment showed that Cistanches Herba extract could significantly improve skeletal muscle atrophy in mice to relieve CRF. The in vitro experiment showed that Cistanches Herba extract could significantly reduce the content of intracellular ROS, the percentage of mitochondrial fragmentation, and the protein expression of Beclin-1 and increase the number of autophagosomes and the protein expression of HIF-1α and BNIP3L. Cistanches Herba showed a good anti-CRF effect, and its mechanism may be related to the key target proteins in the HIF-1α signaling pathway.
Animals ; Mice ; Cistanche ; Network Pharmacology ; Beclin-1 ; Reactive Oxygen Species ; Plant Extracts ; Drugs, Chinese Herbal/pharmacology* ; Molecular Docking Simulation ; Medicine, Chinese Traditional ; Neoplasms/genetics*