A probabilistic knowledge graph for target identification.

Early identification of safe and efficacious disease targets is crucial to alleviating the tremendous cost of drug discovery projects. However, existing experimental methods for identifying new targets are generally labor-intensive and failure-prone. On the other hand, computational approaches, especially machine learning-based frameworks, have shown remarkable application potential in drug discovery. In this work, we propose Progeni, a novel machine learning-based framework for target identification. In addition to fully exploiting the known heterogeneous biological networks from various sources, Progeni integrates literature evidence about the relations between biological entities to construct a probabilistic knowledge graph. Graph neural networks are then employed in Progeni to learn the feature embeddings of biological entities to facilitate the identification of biologically relevant target candidates. A comprehensive evaluation of Progeni demonstrated its superior predictive power over the baseline methods on the target identification task. In addition, our extensive tests showed that Progeni exhibited high robustness to the negative effect of exposure bias, a common phenomenon in recommendation systems, and effectively identified new targets that can be strongly supported by the literature. Moreover, our wet lab experiments successfully validated the biological significance of the top target candidates predicted by Progeni for melanoma and colorectal cancer. All these results suggested that Progeni can identify biologically effective targets and thus provide a powerful and useful tool for advancing the drug discovery process.

Optimal time window for minimally invasive surgery in treating spontaneous intracerebral hemorrhage in the basal ganglia region: a multicenter and retrospective study.

BACKGROUND: The current treatment spontaneous intracerebral hemorrhage (sICH) is limited. AIM: To determine the optimal time window for minimally invasive surgery in patients with sICH. MATERIALS AND METHODS: sICH patients with a hematoma volume of 30-80 mL in the basal ganglia region were included in our study. A total of 357 patients were divided into groups according to different operative times from ICH onset (group 1: 0-6 h, group 2: 6-12 h, group 3: >12 h) and hematoma volumes (30-50 mL and >50 mL). All patients were followed-up for three months' post-operation, and their clinical outcomes were compared. RESULTS: In the three groups of patients with hematoma volumes of 30-50 mL, the rebleeding and mortality rate were higher in group 1 than groups 2 and 3 (p < .05). The activities of daily living evaluated by Barthel Index (BI) three months' post-operation was significantly lower in group 3 than other groups (p < .05) and group 2 had the highest proportion of good outcomes. Among the patients with the hematoma volumes of 50-80 mL, the rebleeding risk was higher in group 1 than groups 2 and 3 (p < .05). However, there were no significant differences in mortality rates among these three groups. Moreover, group 1 had significantly higher BI than groups 2 and 3 (p < .05). CONCLUSIONS: Minimally invasive surgery is safe and effective in patients with sICH. 6-12 h after sICH onset is the optimal surgical window for patients with hematoma volumes of 30-50 mL, while ultra-early (≤6 h) may achieve better results in patients with hematoma volumes of >50 mL.

CELF4 regulates spine formation and depression-like behaviors of mice.

Chronic social stress is closed related to major depressive disorder, torturing millions of people and may destroy their lives. The prefrontal cortex is one of the core brain areas involved in pathological development and behavior changes in depression. CELF4 is a neuronal RNA-binding protein and plays an essential role in RNA processing. It is closely related to some neurological disorders, including seizures and neuroticism. Most recently, GWAS analysis indicates it is one of the significant genes associated with depression. Nonetheless, we are still unknown whether and how CELF4 gets involved in depression. Here, we reported that the protein and mRNA expression levels of CELF4 in the PFC were decreased in the CSDS depression model, as well as the spine number. Furthermore, we disturbed CELF4 expression in the PFC by using the AAV-shCELF4 virus. Unexpectedly, the spine number showed a decrease in PFC because of the impaired CELF4 expression, and the AAV-shCELF4 mice displayed depression-like behaviors. Our results suggest that CELF4 is critical for spine number and acts a critical role in depression-like behaviors of mice.

PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy.

Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment. However, the physiological functions of PD-L1 on DCs remain incompletely understood. Here, we explored the roles of PD-L1 signaling during immunogenic chemotherapy. We found that antitumor efficacy was dramatically reduced in the absence of PD-L1 on DCs. Chemotherapy reshaped the tumor immune microenvironment, particularly the DC compartment. In the absence of PD-L1, DCs were more susceptible to the cytotoxicity induced by chemotherapy. Mechanistically, loss of PD-L1 led to the downregulation of SLC7A11, resulting in increased lipid peroxidation that caused DCs to succumb to ferroptosis and dampened antitumor immune responses. Mice with Pdl1-deficient DCs were less efficient at priming T cells during chemotherapy. In cancer patients, a higher level of PD-L1 on DCs correlated with better prognosis after immunogenic chemotherapy. Collectively, these findings reveal an underappreciated role of PD-L1 in orchestrating DC survival, which is critical during chemoimmunotherapy.

Effect of Cyclotorsion Compensation in Small Incision Lenticule Extraction Surgery for the Correction of Myopic Astigmatism: A Systematic Review and Meta-Analysis.

INTRODUCTION: Small incision lenticule extraction (SMILE) has made notable advancements in addressing myopic astigmatism. Nevertheless, the potential impact of cyclotorsion on surgical outcomes cannot be overlooked. This study aims to assess the effectiveness of cyclotorsion compensation technology in SMILE surgery for the correction of myopic astigmatism, examining its influence on postoperative visual quality. METHODS: A systematic review and meta-analysis were conducted. A comprehensive literature search was performed using databases, including PubMed, Web of Science, EMBASE, Cochrane Library, EBSCO, Scopus, CNKI, VIP, and Wan Fang. Studies meeting the criteria were selected and included. Data were independently extracted by three authors. Clinical outcome parameters were analyzed using Review Manager version 5.3. RESULTS: This meta-analysis included ten studies. The results showed that, compared with the control group (cyclotorsion compensation was not performed in SMILE), the following indicators in the cyclotorsion compensation group were: residual astigmatism (RA) [weighted mean difference (MD) = 0.73, 95% confidence interval (CI) + 0.26 to + 1.19, P = 0.002], spherical equivalent (SE) (MD = 1.99, 95% CI + 0.77 to + 3.21, P = 0.001), coma (MD = -0.06, 95% CI -0.08 to -0.04, P < 0.00001), higher-order aberrations (HOAs) (MD = -0.04, 95% CI -0.06 to -0.02, P < 0.0001), follow-up 6-month angle of error (AE) (MD = -2.67, 95% CI -3.71 to -1.63, P < 0.00001), and follow-up 6-month uncorrected distance visual acuity (UDVA) (MD = -0.05, 95% CI -0.08 to -0.01, P = 0.005), and the differences in results were statistically significant. However, the differences among correction index, index of success (IOS), targeted induced astigmatism (TIA), magnitude of error (ME), and spherical aberration (SA) were not statistically significant. CONCLUSION: Cyclotorsion compensation proves to be effective and predictable for correcting myopic astigmatism. The cyclotorsion compensation group demonstrated advantages over the control group in terms of postoperative residual astigmatism, and it induced fewer coma aberrations. Whether cyclotorsion compensation can lead to better visual quality remains to be seen, and further research on correcting myopic astigmatism through cyclotorsion compensation is warranted.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells.

BACKGROUND: Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy. METHODS: We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo. RESULTS: Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery. CONCLUSIONS: Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.

Reduction of Midline Shift and Short-Term Mortality Following Minimal Invasive Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage: A Retrospective and Case-Control Series.

OBJECTIVE: Currently, the treatment of spontaneous intracerebral hemorrhage (sICH) is limiting, especially in patients with midline shift and supratentorial hemorrhage. Here, we investigated the clinical value of minimally invasive surgery (MIS) in patients with midline shift and supratentorial sICH by observing the consciousness state, midline shift, and short-term mortality. METHODS: A total of 124 supratentorial sICH patients with midline shift, hematoma volume >30 mL and <150 mL were included in this study. Based on treatment methods, the enrolled patients were divided into minimally invasive surgical (MIS) (group 1, n = 61) and conservative (group 2, n = 63) treatment groups. Measurements of midline shift and state of consciousness using the Glasgow Coma Scale (GCS) score were performed on day 2 following treatment. Additionally, mortality, adverse events, and neurologic recovery (modified Rankin Scale score) in each group were observed after 1 month. RESULTS: On postoperative day 2, the recovery rates of midline shift and consciousness state in group 1 patients were 59.02% and 50.82%, respectively, significantly higher than group 2, 26.98% and 25.40% (P < 0.01). By comparing death, adverse events, and neurologic function recovery of the 2 groups within 1 month postoperative, we observed a significantly lower fatality rate in group 1 (16.39%; 10 cases) than group 2 (33.33%; 21 cases) (P < 0.05). No significant difference of the adverse event rates was observed between groups 1 and 2 (19.67% [12 cases] vs. 19.05% [12 cases]). In addition, neurologic function recovery also had no significant difference between the 2 groups (P > 0.05). CONCLUSIONS: MIS could reduce early-stage midline shift, improve consciousness state and reduce short-term mortality in patients with supratentorial sICH.

The structures of two polysaccharides from Angelica sinensis and their effects on hepatic insulin resistance through blocking RAGE.

This study found two novel homogeneous polysaccharides from Angelica sinensis, APS-1I and APS-2II, binding to RAGE with a dissociation constant of 2.02 ± 0.2 and 85.92 ± 0.2 µM, respectively. APS-1I is a 17.0 kDa heteropolysaccharide, whose backbone is composed of α-1,6-Glcp, α-1,3,6-Glcp, α-1,2-Glcp, α-1,4-Galp, and α-1,3-Rhap, and whose two branches contain α-1,3,5-Araf, α-1,3-Araf, α-1,4-Galp, ß-1,3-Galp, and ß-1,4-Glcp. APS-2II is a 10.0 kDa linear glucan, that contains α-1,6-Glcp, α-1,3-Glcp, α-1,2-Glcp, and α-T-Glcp. In vitro, APS-1I demonstrated better promotion on glucose absorption and stronger repression on p-IRS-1 (Ser307), p-IRS-2 (Ser731), p-JNK, and p-P38 than APS-2II in insulin resistance (IR)-HepG2 cells. Furthermore, APS-1I treatment couldn't further decrease the inhibition on the phosphorylation of JNK and P38 produced by RAGE siRNA in IR-HepG2 cells. In vivo, APS-1I markedly improved IR and reversed the livers RAGE-JNK/p38-IRS signaling in high-fat-diet and streptozotocin-induced diabetic rats, suggesting that APS-1I could be a potential agent for improving IR in type 2 diabetes.

Structures and anti-melanoma activities of two polysaccharides from Angelica sinensis (Oliv.) Diels.

Polysaccharide is one of the necessary macromolecules in life activities, and it is also a very promising natural product for tumor prevention and treatment. In this study, two homogeneous polysaccharides (APS-4I and APS-4II) were isolated from Angelica sinensis (Oliv.) Diels. APS-4I was a linear glucan with molecular weight of 16.1 kDa, which was composed of 88.4% α-1,6-Glcp, 4.1% α-1,2-Glcp, 3.9% α-1,3-Glcp, and 2.8% α-T-Glcp. APS-4II was a novel polysaccharide with molecular weight of 11.1 kDa, which consisted of 55.4% α-1,6-Glcp, 10.4% α-1,3,5-Araf, 8.7% α-T-Araf, 9.2% α-1,5-Araf, 4.0% α-1,3-Araf, 3.6% α-1,4-Galp, and 9.1% ß-1,3-Galp. NMR results demonstrated that APS-4II has a backbone composed of →6)-α-Glcp-(1 → 6)-α-Glcp-(1 → 5)-α-Araf-. (1 → 5)-α-Araf-(1 → 3,5)-α-Araf-(1 → 3)-ß-Galp-(1 → 3)-ß-Galp-(1 → 4)-α-Galp-(1 → 3)-α-Araf-(1 → 3,5)-α-Araf-(1→. Both APS-4I and APS-4II inhibited the tumor growth of B16-bearing mice, and the suppressive effect of APS-4II reached 64.7 ± 7.3%. Meanwhile, there were higher lymphocyte numbers and the levels of IL-2, IFN-γ, and TNF-α in peripheral blood of APS-4II-treated mice than those in APS-4I-treated mice. Furthermore, APS-4II showed a higher inhibitory effect on the proliferation of B16 cells and stronger promoting effects on the proliferation of splenocytes, the phagocytosis of peritoneal macrophages, and the cytotoxicity of NK cells. These results demonstrated that APS-4II could be a promising therapeutic agent for melanoma.

Leukemia cells apoptosis by a newly discovered heterogeneous polysaccharide from Angelica sinensis (Oliv.) Diels.

Galectin-3 (Gal-3) is a potential target for acute myeloid leukemia therapeutics which contains a carbohydrate-recognition domain. However, the development of polysaccharide inhibitors against Gal-3 is insufficient. In this research, we found a polysaccharide from Angelica sinensis (Oliv.) Diels, named APS-2I, that can bind to Gal-3 with dissociation constant (Kd) of 9.35 ±â€¯0.3 µM and activate the intrinsic apoptosis pathways to induce leukemia cells apoptosis. APS-2I is a homogeneous polysaccharide with a molecular weight of 7.2 × 105 Da, that composes of mannose, rhamnose, galacturonic acid, glucose, galactose and arabinose with a ratio of 4:5:1:10:23:39. In addition, a galactosidase digested fraction of APS-2I named G-4 showed higher affinity to Gal-3 with the Kd of 1.97 ±â€¯0.7 µM and higher apoptosis inducing effect on leukemia cells, which demonstrated that G-4 contains the bio-active structural region of APS-2I. This study provides effective basis for structural analysis and the anti-leukemia mechanism of Angelica polysaccharide APS-2I.