CXCR4 is required for the quiescence of primitive hematopoietic cells

The quiescence of hematopoietic stem cells (HSCs) is critical for preserving a lifelong steady pool of HSCs to sustain the highly regenerative hematopoietic system. It is thought that specialized niches in which HSCs reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by the niche and how these niche signals regulate such a balance. We report that CXCL12 produced by bone marrow (BM) stromal cells is not only the major chemoattractant for HSCs but also a regulatory factor that controls the quiescence of primitive hematopoietic cells. Addition of CXCL12 into the culture inhibits entry of primitive hematopoietic cells into the cell cycle, and inactivation of its receptor CXCR4 in HSCs causes excessive HSC proliferation. Notably, the hyperproliferative Cxcr4−/− HSCs are able to maintain a stable stem cell compartment and sustain hematopoiesis. Thus, we propose that CXCR4/CXCL12 signaling is essential to confine HSCs in the proper niche and controls their proliferation

The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity

The chemokine receptor CXCR4 is expressed in B cells at multiple stages of their development. CXCR4 function in humoral immunity has not been fully investigated. We have generated gene-targeted mice in which CXCR4 can be selectively inactivated in B cells and have shown that it is required for retention of B cell precursors in the bone marrow. CXCR4-deficient B cell precursors that migrated prematurely became localized in splenic follicles despite their unresponsiveness to CXCL13. Concomitantly, mature B cell populations were reduced in the splenic marginal zone and primary follicles, and in the peritoneal cavity in the mutant animals, as were T-independent antibody responses. In addition, aberrant B cell follicles formed ectopically in intestinal lamina propria around Peyer's patches. These findings establish an important role for CXCR4 in regulating homeostasis of B cell compartmentalization and humoral immunity

Electroacupuncture Improves Cerebral Vasospasm and Functional Outcome of Patients With Aneurysmal Subarachnoid Hemorrhage

Cerebral vasospasm is the major cause of a poor outcome after aneurysmal subarachnoid hemorrhage (aSAH), and effective treatments for vasospasm are limited. The purpose of this study was to research the impact of electroacupuncture (EA) on cerebral vasospasm and the outcomes of patients with aSAH. A total of 60 age- and sex-matched aSAH patients were collected from Ningbo First Hospital between December 2015 and June 2017. All patients were given a basic treatment of nimodipine and randomized into two groups. The study group was treated with EA therapy on the Baihui (GV20) acupoint, and the control group was given mock transcutaneous electrical nerve stimulation. Cerebral vasospasm was measured by computed tomographic perfusion (CTP) and transcranial doppler (TCD). The mean flow velocity (MFV) in the middle cerebral artery (MCA), cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) of the patients were analyzed. The CBV and MTT exhibited significant differences between the study and control groups on the 1st (p = 0.026 and p = 0.001), 7th (p = 0.020 and p < 0.001), and 14th (p = 0.001 and p < 0.001) day after surgery, whereas CBF exhibited statistical significance only on the 14th day after surgery (p = 0.002). The MFV in MCA were significantly reduced after EA treatment in all patients (all p < 0.001). Additionally, the MFV in the MCA in patients treated with EA were considerably reduced compared with those of the control group (3rd day p = 0.046; 5th day, p = 0.010; 7th day, p < 0.001). Moreover, better outcomes were noted in the EA-treated group for the 1st month (p < 0.001) and 3rd month (p = 0.001) after surgery than in the control group. In conclusion, EA represents a potential method to treat cerebral vasospasm after aSAH and can improve the outcomes of patients with aSAH

An Essential Role of the Cytoplasmic Tail of CXCR4 in G-Protein Signaling and Organogenesis

CXCR4 regulates cell proliferation, enhances cell survival and induces chemotaxis, yet molecular mechanisms underlying its signaling remain elusive. Like all other G-protein coupled receptors (GPCRs), CXCR4 delivers signals through G-protein-dependent and -independent pathways, the latter involving its serine-rich cytoplasmic tail. To evaluate the signaling and biological contribution of this G-protein-independent pathway, we generated mutant mice that express cytoplasmic tail-truncated CXCR4 (ΔT) by a gene knock-in approach. We found that ΔT mice exhibited multiple developmental defects, with not only G-protein-independent but also G-protein-dependent signaling events completely abolished, despite ΔT's ability to still associate with G-proteins. These results reveal an essential positive regulatory role of the cytoplasmic tail in CXCR4 signaling and suggest the tail is crucial for mediating G-protein activation and initiating crosstalk between G-protein-dependent and G-protein-independent pathways for correct GPCR signaling

Coacervation of Cationic Gemini Surfactant with <i>N</i>‑Benzoylglutamic Acid in Aqueous Solution

Coacervation of cationic gemini surfactant hexamethylene-1,6-bis­(dodecyldimethylammonium bromide) (12–6–12) with pH-sensitive <i>N</i>-benzoylglutamic acid (H₂Bzglu) has been investigated by potentiometric pH-titration, turbidity titration, dynamic light scattering (DLS), isothermal titration calorimetry (ITC), TEM, ¹H NMR, and light microscopy. Phase boundaries of the 12–6–12/H₂Bzglu mixture were obtained over the pH range from 2 to 9 and in the H₂Bzglu concentration range from 30.0 to 50.0 mM at pH 4.5. When the H₂Bzglu concentration is beyond 30.0 mM, the 12–6–12/H₂Bzglu mixed solution undergoes the phase transitions from soluble aggregate, to precipitate, coacervate, and soluble aggregate again as pH increases. The results indicate that coacervation occurs at extremely low 12–6–12 concentration and lasts over a wide surfactant range, and can be enhanced or suppressed by changing pH, 12–6–12/H₂Bzglu molar ratio and H₂Bzglu concentration. The coacervates present a disorderly connected lay structure. Coacervation only takes place at pH 4–5, where the aggregates are nearly charge neutralized, and a minimum H₂Bzglu concentration of 30.0 mM is required for coacervation. In this pH range, H₂Bzglu mainly exist as HBzglu^–. The investigations on intermolecular interactions indicate that the aggregation of 12–6–12 is greatly promoted by the strong electrostatic and hydrophobic interactions with the HBzglu^– molecules, and the interaction also promotes the formation of dimers, trimers, and tetramers of HBzglu^– through hydrogen bonds. The double chains of 12–6–12 and the HBzglu^– oligomers can play the bridging roles connecting aggregates. These factors endow the mixed system with a very high efficiency in generating coacervation

Pharmacogenomics of Leukotriene Modifiers: A Systematic Review and Meta-Analysis

Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager (Revman, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark) and R language and environment for statistical computing (version 4.1.0 for Windows, R Core Team, Vienna, Austria) software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05, p = 0.31). AA homozygotes had smaller improvements in parameters pertaining to lung functions (−0.14, 95%CI: −0.23 to −0.05, p = 0.002) in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) (−0.11, 95%CI: −0.14 to −0.08, p < 0.00001), but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response

Physicians&rsquo; Knowledge, Attitude, and Experience of Pharmacogenomic Testing in China

(1) Background: As prescribers, physicians play a decisive role in applying and promoting pharmacogenomic (PGx) testing in clinical practices. So far, little is known about physicians&rsquo; perspectives on PGx testing in China. The aim of this study was to assess physicians&rsquo; knowledge of, attitude towards, and experience of PGx testing in China. (2) Methods: A 39-question online survey was developed. Participants were physicians recruited through two platforms, MEDLINKER and &ldquo;Dazhuanjia&rdquo;. (3) Results: A total of 450 respondents completed the survey and 366 questionnaires were eligible for analysis based on the inclusion criteria. Among all included physicians, 275 (75.1%) had heard of PGx testing before. More than half rated their knowledge of PGx testing as &ldquo;Fair&rdquo; (61.5%) while 20.0% chose &ldquo;Excellent&rdquo; or &ldquo;Good&rdquo; and 18.6% chose &ldquo;Poor&rdquo; or &ldquo;Terrible&rdquo;. &ldquo;Guidelines, consensus, and treatment paths for disease diagnosis and treatment&rdquo; (72.7%) were the most preferred sources of information about PGx testing. Respondents were confident in their personal capacity to conduct PGx, with an average score of 3.30 &plusmn; 0.09 (out of 5.00). Most respondents (75.6%) believed that PGx could &ldquo;help to improve efficacy and reduce the incidence of adverse reactions&rdquo;. Targeted cancer therapy (score 78.95 &plusmn; 1.26 out of 100) was considered the field where PGx testing had its highest value. Lack of professionals and knowledge (n = 186, 67.6%), high costs of testing (n = 170, 61.8%), and lack of hospitals to offer PGx testing (n = 166, 60.4%) were identified as the primary obstacles to increasing the uptake of PGx testing in China. Academic conference (n = 213, 72.4%) was considered the most efficient way for physicians to obtain information about PGx testing. (4) Conclusions: Physicians in China have poor knowledge about PGx testing; nonetheless, they generally had confidence in their capacity to order PGx testing and positive attitudes towards the use of PGx testing in routine clinical practices. Future efforts to promote the uptake of PGx testing should focus on foundational education and practical training