Letter to the editor: 1H, 13C and 15N resonance assignments of Aquifex aeolicus shikimate kinase in complex with the substrate shikimate.
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Bacteria↗
Biomedical subjects
Q Liu
Publications and source records attributed to Q Liu.
Cloning, tissue expression pattern and genomic organization of latexin, a human homologue of rat carboxypeptidase A inhibitor.
Latexin, a carboxypeptidase A inhibitor, is expressed in a cell type-specific manner in both central and peripheral nervous systems in the rat. It is used as a molecular marker for the regional specification of the neocortex. In this study, a cDNA was isolated from a human fetal brain cDNA library. The cDNA (LXN) contains an open reading frame encoding 222 amino acids. The comparison between the deduced amino acid sequences of LXN and latexins of rat and mouse revealed high sequence identity (84.2 and 84.7%, respectively). Northern blot analysis showed that LXN was expressed as a transcript of 1.3 kb in 15 out of 16 tissues examined, except in peripheral blood leukocyte. The expression levels were high in heart, prostate, ovary, kidney, pancreas, and colon, moderate or low in other tissues including brain. It is noteworthy that the tissue distribution of human LXN differs greatly to that of its homologue in the model animal, rat latexin. In addition, the LXN gene contains at least 6 exons and spans 5.9 kb according to the genomic sequence of the clone RP11-79M21 and the gap sequence cloned in this paper. LXN was assigned to 3q25-q26.2 according to the position of the marker SHGC-35682 found adjacent to LXN gene.
Amino Acid Sequence↗
Effects of sodium on agonist efficacy for G-protein activation in mu-opioid receptor-transfected CHO cells and rat thalamus.
1. Sodium ions inhibit spontaneous G(i)/G(o)-coupled receptor activity and promote agonist-induced responses in vitro. The effects of sodium on the relative efficacy of opioid agonists for G-protein activation was measured by guanosine-5'-O-(gamma-(35)S)-triphosphate ([(35)S]-GTPgammaS) binding in membranes from two mu-opioid receptor-containing systems: CHO cells stably transfected with mouse mureceptors (mMOR-CHO cells) and rat thalamus. 2. NaCl inhibited basal [(35)S]-GTPgammaS binding in both systems, and this effect was partially mimicked by KCl. In mMOR-CHO membranes, net [(35)S]-GTPgammaS binding stimulated by partial but not full agonists was inhibited by NaCl with a potency that was inversely proportional to agonist efficacy. Monovalent cations were required for agonist-stimulated [(35)S]-GTPgammaS binding in this system, and increasing NaCl concentrations magnified relative efficacy differences among agonists. 3. In thalamic membranes, which contain a lower receptor:G-protein ratio than mMOR-CHO cells, similar monovalent cation effects were observed, with two exceptions: (1) [(35)S]-GTPgammaS binding stimulated by both full and partial agonists was inhibited by NaCl; and (2) monovalent cations were not required to observe agonist-stimulated [(35)S]-GTPgammaS binding. 4. Basal [(35)S]-GTPgammaS binding stimulated by the absence of monovalent cations resembled that of agonist-stimulated binding and was blocked by pretreatment of mMOR-CHO cells with pertussis toxin. 5. These results indicate that sodium inhibits spontaneous and agonist-occupied mu receptor-mediated G-protein activation in a manner inversely proportional to the efficacy of the agonist, and that spontaneous mu receptor activity and the relative efficacy of partial agonists acting at these receptors are both increased by increases in the stoichiometric ratio of receptors:G-proteins.
Animals↗
Expression and function of MIP-2 are reduced by dexamethasone treatment in vivo.
1. The objective of this study was to examine the effect of dexamethasone on tumour necrosis factor-alpha (TNF-alpha)-induced expression and function of macrophage inflammatory protein-2 (MIP-2) and neutrophil recruitment. For this purpose, we used air pouches raised on the dorsal skin of C57/B16 mice. 2. Initially, we examined the dose-response (0.01 - 0.5 microg ml(-1)) and kinetics (0 - 24 h) of TNF-alpha-induced leukocyte accumulation. The cellular response was maximal at 0.1 microg ml(-1) of TNF-alpha and 4 h after challenge and comprised more than 90% neutrophils. 3. Intraperitoneal (i.p.) pretreatment with 10 mg kg(-1) of dexamethasone for 2 h, but not 1 mg kg(-1), reduced TNF-alpha-induced recruitment of neutrophils by 87%. Administration of dexamethasone had no effect on the expression of CD18 on neutrophils. 4. TNF-alpha (0.1 microg ml(-1)) markedly increased the levels of MIP-2 in the air pouches 1 h after challenge and after 4 h the MIP-2 values returned to baseline. Notably, 2 h pretreatment with dexamethasone (10 mg kg(-1), i.p.) reduced MIP-2 expression by 65% in response to TNF-alpha (0.1 microg ml(-1)). On the other hand, dexamethasone treatment did not change the levels of interleukin-10 (IL-10) in the pouch exudate. 5. Administration of recombinant MIP-2 increased neutrophil accumulation at 0.5 and 1.0 microg ml(-1) after 4 h of challenge. Dexamethasone pretreatment for 2 h (10 mg kg(-1), i.p.) abolished the MIP-2-induced recruitment of neutrophils. 6. Taken together, our data demonstrate that dexamethasone may downregulate TNF-alpha-induced neutrophil recruitment by inhibiting both the expression and function of MIP-2 in vivo.
Animals↗
Indirect determination of thiocyanate with ammonium sulfate and ethanol by extraction-flotation of copper.
A new method for the indirect determination of thiocyanate with ammonium sulfate and ethanol by extraction-flotation of copper in the presence of ascorbic acid is described. A small amount of Cu(II) is reduced to Cu(I) by ascorbic acid, then Cu(I) is precipitated with SCN-. In the course of phase separation of ethanol from water, the precipitated CuSCN stays in the interface of ethanol and water. A good linear relationship is observed between the flotation yield of Cu(II) and the amount of SCN-. Using 1.0 ml of 1 x 10(-3) M ascorbic acid solution, 50 micrograms of Cu(II), 3.5 g of (NH4)2SO4 and 3.0 ml of ethanol with a total volume of 10 ml, the concentration of thiocyanate could then be determined by determining the flotation yield of Cu(II). The detection limit for thiocyanate is 5 x 10(-5) M. Every parameter was optimized and the reaction mechanism was studied. The method is simple and rapid and it was successfully applied to the determination of thiocyanate in urine and saliva of smokers and non-smokers and in venous blood of patients infused with sodium nitroprusside.
Ammonium Sulfate↗
Influence of alpha-adrenoceptor blockade on antigen- and propranolol-induced bronchoconstriction in guinea-pigs in vivo.
1. Beta-adrenoceptor antagonists, such as propranolol, can provoke severe bronchoconstriction only in asthmatic subjects. Recently, we developed a guinea-pig model of propranolol-induced bronchoconstriction (PIB) and the purpose of this study was to investigate the role of alpha-adrenergic nerve pathways in this reaction. 2. Phentolamine administered after an antigen challenge did not inhibit PIB; however, its administration before the antigen challenge significantly inhibited the antigen-induced bronchoconstriction and also bronchoconstriction induced by methacholine inhalation. 3. We conclude that the alpha-adrenergic nerve system is not involved in the development of PIB following allergic reaction in our guinea-pig model.
Administration, Inhalation↗
Analysis of mRNA decay and rRNA processing in Escherichia coli in the absence of RNase E-based degradosome assembly.
We demonstrate here that the assembly of the RNase E-based degradosome of Escherichia coli is not required for normal mRNA decay in vivo. In contrast, deletion of the arginine-rich RNA binding site (ARRBS) from the RNase E protein slightly impairs mRNA decay. When both the degradosome scaffold region and the ARRBS are missing, mRNA decay is dramatically slowed, but 9S rRNA processing is almost normal. An extensive RNase E truncation mutation (rnedelta610) had a more pronounced mRNA decay defect at 37 degrees C than the temperature-sensitive rne-1 allele at 44 degrees C. Taken together, these data suggest that the inviability associated with inactivation of RNase E is not related to defects in either mRNA decay or rRNA processing.
Endoribonucleases↗
Primary cutaneous B-cell lymphoma in Japanese patients.
Primary cutaneous B-cell lymphoma (PCBCL) is a rare group of lymphoproliferative disorders. There have been few reports of Japanese patients with PCBCL, so the present study investigated the clinicopathological and immunological features and Bcl-2 gene rearrangement and protein expression in 28 Japanese patients with PCBCL. According to the Revised European-American Lymphoma (REAL) classification, there were 25 diffuse large B-cell lymphomas (DLBCL), one Burkitt type lymphoma, one lymphoblastic lymphoma and one marginal zone cell lymphoma. Of the 25 DLBCL, 17 were in males and eight in females, with an average age of 69.4 years. Follow-up data were available in 19 cases of DLBCL of which seven died and 12 were alive. The overall 5-year survival rate was 61%. Cases of DLBCL involving the legs were found to have poorer clinical outcomes; two of four cases with leg lesions died, with a mean survival of 13 months. Of 14 cases with non-leg lesions, four died, and the mean survival was 38.9 months. Only one case of Burkitt type lymphoma was CD10 positive. Bcl-2 rearrangement was not observed in 13 cases studied by polymerase chain reaction. Bcl-2 expression was observed in nine of 13 cases studied. All five cases with leg lesions exhibited Bcl-2 expression, but four of six cases with non-leg lesions also expressed the protein. These results show that DLBCL is the most frequent subtype of PCBCL in Japanese patients and that the prognosis of Japanese patients with DLBCL is worse than that of reported European cases. The study also found that PCBCL was frequently associated with Bcl-2 expression, which was not site-confined, and that there was no evidence for a follicular center origin of PCBCL.
Adult↗
Azido- and isothiocyanato-substituted aryl pyrazoles bind covalently to the CB1 cannabinoid receptor and impair signal transduction.
3-Azidophenyl- and 3-isothiocyanatophenyl-and 2-(5'-azidopentyl)- and 2-(5'-isothiocyanatopentyl)pyrazoles were synthesized to determine whether these compounds could behave as covalently binding ligands for the CB1 cannabinoid receptor in rat brain membranes. Heterologous displacement of [3H]CP55940 indicated that the apparent affinity of these compounds for the CB1 receptor was similar to that of the parent compound, SR141716A, with the exception of the 3-isothiocyanato derivatives, which showed a 10-fold loss of affinity. The 3-azidophenyl and 3-isothiocyanatophenyl compounds behaved as antagonists against the cannabinoid agonist desacetyllevonantradol in activation of G proteins [guanosine 5'-O-(y-[35S]thio)triphosphate ([35S]GTPgammaS) binding] and regulation of adenylyl cyclase. The 2-(5'-azidopentyl)- and 2-(5'-isothiocyanatopentyl)pyrazoles were poor antagonists for [35S]GTPgammaS binding, and both compounds failed to antagonize the cannabinoid regulation of adenylyl cyclase. After incubation with the isothiocyanato analogues or UV irradiation of the azido analogues, the 3-substituted aryl pyrazoles formed covalent bonds with the CB1 receptor as evidenced by the loss of specific binding of [3H]CP55940. In the case of the isothiocyanato analogues, the log concentration-response curve for cannabinoid-stimulated [35S]GTPgammaS binding was shifted to the right, indicating that loss of receptors compromised signal transduction capability. These irreversibly binding antagonists might be useful tools for the investigation of tolerance and receptor down-regulation in both in vitro and in vivo studies.
Adenylyl Cyclases↗
Impact of secondary cytoreductive surgery on survival of patients with advanced epithelial ovarian cancer.
AIMS: To investigate the impact on survival of secondary cytoreduction for advanced epithelial ovarian cancer and variables influencing redebulking surgical outcome. METHODS: Between 1986 and 1997, 106 patients who received secondary cytoreductive surgery and consequent second-line chemotherapy for stages III and IV epithelial ovarian cancer were retrospectively reviewed. The optimal residual disease cut-off was 1.0 cm. The Cox proportional regression model and logistic stepwise regression were used in statistical processing of the data. RESULTS: The median age of the patients was 50 years (range, 26-77 years). Optimal secondary cytoreduction was achieved in 46 of 106 patients (43.4%). There was a significant difference in survival between patients who were optimally cytoreduced compared to those suboptimaly cytoreduced, with an estimated median survival in the optimal group of 20 months vs 8 months in the suboptimal group ((2)=42.03, P=0.0000). When factorized, patients had significant survival benefit from optimal secondary cytoreduction for recurrent disease and interval cytoreduction. Survival was adversely influenced by progression-free interval < or =12 months (P=0.0078), residual disease >1 cm (P=0.0001) and presence of refractory ascites (P=0.0001). The probability of successful redebulking surgery was affected by presence of refractory ascites (P=0.0023) in all 106 patients and by the ascites (P=0.0072) and residual disease at initial operation in recurrent disease (P=0.0096). CONCLUSION: Secondary surgical cytoreduction surgery significantly lengthened survival for patients with recurrent epithelial ovarian cancer or those receiving interval cytoreduction. Patients with refractory ascites, however, were not suitable for aggressive secondary surgery, and redebulking surgery for those with residual disease of >1.0 cm after primary operation should be considered prudently in recurrent disease.
Adult↗
Association between level of delivery hospital and neonatal outcomes among South Carolina Medicaid recipients.
OBJECTIVE: The purpose of this study was to examine relationships between level of delivery hospital and neonatal mortality rate, length of stay, and Medicaid reimbursement. STUDY DESIGN: This was a retrospective cohort study of 2560 infants with birth weights between 500 and 1499 g who were born between 1991 and 1995 to South Carolina mothers and whose care was covered by Medicaid. RESULTS: The relative risk of neonatal death for infants born in level I and II hospitals (relative risk, 1.9; 95% confidence interval, 1.6-2.2) but not level II hospitals with 24-hour neonatology coverage (relative risk, 1.2; 95% confidence interval, 0.7-1.9) was higher than that for infants born in level III hospitals. Compared with infants born in level III hospitals mean length of stay was longer and Medicaid reimbursement was similar for infants born in level I and II hospitals. Among infants born in level II hospitals with 24-hour neonatology coverage length of stay was shorter and Medicaid reimbursement was lower. CONCLUSION: Infants born in level I and II hospitals had higher neonatal mortality rates and longer stays than did infants born in level III hospitals, despite similar Medicaid reimbursement.
Cohort Studies↗
Glycoprotein IIb-IIIa-liposomes bind fibrinogen but do not undergo fibrinogen-mediated aggregation.
Although platelet cross-bridging is mediated primarily by the binding of fibrinogen to its activated membrane receptor, glycoprotein (GP) IIb-IIIa*, such an interaction may not be sufficient to support the aggregation process. As this question could potentially be answered by reconstituting GPIIb-IIIa* into a non-platelet environment such as liposomes, a protocol was developed for the generation of large lipid vesicles containing purified GPIIb-IIIa*. Flow cytometric techniques confirmed that the receptor was present in the lipid bilayer and were used to evaluate the characteristics of fibrinogen binding to the liposomes, which like fibrinogen-platelet interactions exhibited specificity, saturability, time dependence and calcium dependence. No fibrinogen-specific aggregation of GPIIb-IIIa* liposomes with stir or shear was observed, as determined by flow cytometric cell counting and microscopic examination of particles. In contrast, activated platelets rapidly bound Fg and rapidly formed large aggregates. The Fg associated with GPIIb-IIIa* in liposomes was 'normally' recognized by two fluorescently labelled antibodies: 4A5, which interacts with the Fg gamma chain C-terminus (residues 400-411) required for Fg-mediated cross-bridging of activated platelets in platelet aggregation (Shiba E, Lindon JN, Kushner L, Matsueda GR, Hawiger J, Kloczewiak M, Kudryk B, Salzman EW. Antibody-detectable changes in fibrinogen adsorption affecting platelet activation on polymer surfaces. Am J Physiol 1991; 260: C965-74), and anti-Fg-RIBS-I, which associates with an epitope on Fg (residues 373-385) expressed upon binding to GPIIb-IIIa. These data suggest that the Fg gamma-terminus is sterically accessible for particle cross-bridging and that an identical conformational change occurs for receptor-bound Fg on both liposomes and platelets. It thus appears that cellular elements aside from GPIIb-IIIa, such as cytoskeletal proteins proposed to be necessary for receptor 'anchoring', play a necessary role in flow-associated platelet aggregation.
Acetates↗
Immune responses to hepatitis C virus structural and nonstructural proteins induced by plasmid DNA immunizations.
DNA-based immunizations have been used to elicit cellular immunity to hepatitis C virus (HCV) proteins in mice. Mice were immunized by intramuscular or intradermal injections of plasmid DNA derived from a near-full-length HCV genotype 1b genomic clone (pRC/B2) or individual genomic clones. These immunizations induced cytotoxic T lymphocytes (CTLs), as revealed in standard chromium-release assays that used syngeneic peptide-pulsed or transfected target cells. These assays identified four CTL epitopes within the capsid, E1, and E2 regions of the polyprotein sequence of HCV genotype 1a that were cross-reactive with HCV genotype 1b. Additionally, CTLs derived from mice immunized with either NS3 or NS5 specifically lysed target cells sensitized to either the genotype 1a or 1b gene products. Nucleic acid immunizations also generated humoral immunity to HCV proteins, as detected by anti-HCV reactivity to NS3 and capsid in ELISAs and immunoblot assays.
Animals↗
High steady-state plasma levels of flt3-ligand in the peripheral blood is a good predictor for poor mobilization of CD34+ PBSC in patients undergoing high-dose chemotherapy and stem cell rescue.
flt3-ligand (flt3-L) is a very effective mobilizer of hematopoietic stem cells (HSC) and is capable of inducing multilineage hematopoietic cell differentiation both in vivo and in vitro. We measured, by ELISA, the plasma peripheral blood flt3-L concentrations in 28 non-Hodgkin's lymphoma (NHL) patients before and after mobilization with three different mobilization regimens, including priming with cyclophosphamide (CY) plus G-CSF, CY plus GM-CSF, and CY plus GM-CSF (8 days) followed by G-CSF. We also determined the levels of flt3-L in the peripheral blood during four apheresis collections and 6 months after transplantation. The steady-state level of flt3-L in NHL patients (n = 18) who mobilized > or =2 x 10(6) CD34+ cells/kg in four apheresis collections was 34 +/- 4 pg/ml and was similar to the levels observed in 10 normal controls (27 +/- 7, p = 0.1) regardless of the mobilization protocol used. In contrast, patients who failed to mobilize a total of >0.4 x 10(6) CD34+ cells/kg in two consecutive apheresis collections (n = 10) had flt3-L levels of 106 +/- 11 pg/ml, significantly higher (p = 0.006) than that of the good mobilizers group, regardless of the mobilization protocol used. Similar results were observed in 29 multiple myeloma (MM) patients. A mean of 23.8 +/- 7.9 pg/ml and 450 +/- 85 pg/ml flt3-L was obtained in the good mobilizers (n = 24) and the nonmobilizers (n = 5) groups of patients, respectively. Statistical analysis revealed a significant difference (p = 0.0006) between the two groups of MM patients, but no correlation was observed between the levels of flt3-L and CD34+ cell/microl, in mobilized peripheral blood. Our results also suggest that measurement of plasma levels of flt3-L before mobilization can be clinically useful to predict for patients with poor mobilization outcome.
Adjuvants, Immunologic↗
Peripheral blood stem cell mobilization with cyclophosphamide in combination with G-CSF, GM-CSF, or sequential GM-CSF/G-CSF in non-Hodgkin's lymphoma patients: a randomized prospective study.
We designed a randomized, prospective three-arm mobilization study to determine the kinetics of peripheral blood stem cell (PBSC) mobilization in 60 non-Hodgkin's lymphoma (NHL) patients primed with cyclophosphamide (CTX) in combination with granulocyte colony-stimulating factor (G-CSF) (arm A), granulocyte-macrophage (GM)-CSF (arm B) or GM-CSF/G-CSF (arm C). We also compared mobilization and transplant-related toxicities, pre- and post-transplant support and the probability of survival among the three arms. To date, 35 patients have been enrolled in the study; 13 patients have been enrolled in arm A, 10 patients in arm B, and 13 patients in arm C. Successful collection of the target of > or = 2 X 10(6) CD34+ cells/kg in one to four apheresis collections was 10/13, 6/10, and 7/12 in arms A, B, and C, respectively. The differences between arms were not statistically significant. The median time to achieve the target CD34+ cells in patients who successfully mobilized the target CD34+ cells was 3 days, 2 days, and 1 day, in patients in arms A, B, and C, respectively. The time for neutrophil engraftment was 11, 10, and 10 days in arms A, B, and C, respectively. The time for platelet engraftment was 11 days for patients in all arms of the study. Most importantly, no significant differences were observed among the three arms in the duration of neutropenic fever, the extent of mucositis, diarrhea, and nausea/vomiting, or in the number of units of platelets or red cells transfused after transplantation. Risk factors associated with poor mobilization were > or = 3 regimens of chemotherapy prior to mobilization, older age, and disease histology (follicular versus diffuse). Therefore, we conclude that the type of growth factor used for mobilization did not play a major role in the outcome of mobilization and recommend mobilizing NHL patients before they receive multiple regimens of chemotherapy.
Adult↗
Inhibition of interleukin-1-induced uveitis and corneal fibroblast proliferation by interleukin-1 blockers.
Interleukin-1 (IL-1) is known to trigger induction of inducible nitric oxide synthase (iNOS) to persistently mass produce nitric oxide (NO) to induce various diseases such as cancer, inflammation, Alzheimer's disease and eye diseases, including uveitis, retinopathy, age-related macular degeneration, glaucoma and myopia. Therefore, IL-1 blockers could become an important class of drugs to fight numerous diseases. Among the many compounds studied so far, 1-methyl hydrazino analogs are among the most promising agents to be developed. A minor structural change of 1-methyl hydrazino group into 1-methyl thiosemicarbazido group enhanced their anti-inflammatory activity but reduced their antiproliferation activity on corneal fibroblast cell growth.
Animals↗
Effects of interleukin-1 blockers on corneal fibroblast proliferation in vitro and ocular inflammation in vivo.
The success of keratorefractive surgical procedures is limited by the wound healing process in the corneal stroma. The proliferation and matrix synthesis of corneal stromal fibroblasts is the central element of the wound healing process that is triggered by an initial inflammation. In order to develop new therapeutic strategies to reduce wound healing intensity, we investigated the effect of newly synthesized interleukin-1 (IL-1) blockers on the proliferation of cultured rabbit corneal fibroblasts and the ocular inflammation induced by IL-1. It was found that the addition of IL-1 blockers, such as CK-135 to CK-145, led to a dose-dependent inhibition of cell proliferation after 24, 48 and 72 hr of incubation. The isotope incorporation study showed that the syntheses ofDNA and mRNA were suppressed whereas that of protein was enhanced or unaffected. These compounds also demonstrated a potent anti-inflammation action in the rat uveitis model. Our results indicate that CK (Chiou-Kumamoto) compounds may be valuable therapeutic agents for the prevention of postoperative complications after corneal keratorefractive surgical procedures.
Animals↗
Evaluation of a new method of small fragment fixation in a medial malleolus fracture model.
OBJECTIVE: To evaluate a new method of small fragment fixation in a medial malleolus fracture model. DESIGN/METHODS: The authors measured the pullout strength, resistance to shear stress, and speed of insertion of 4.0-millimeter partially threaded cancellous screws, 2.4-millimeter smooth K-wires, and a small fragment fixation system with 2.2-millimeter threaded K-wires. Pullout strength was tested in eighty-one synthetic foam blocks and resistance to shear stress in thirty synthetic tibias by use of a servohydraulic testing machine. Six randomized time trials with the threaded K-wires and cancellous screws were also conducted. RESULTS: Pullout strength increased with increasing foam density, increasing insertion depth, and varied with fixation method (p < 0.05). Maximum pullout strengths were as follows: partially threaded cancellous screws, 730+/-4 Newtons; threaded K-wires, 316+/-12 Newtons; and smooth K-wires, 172 +/-5 Newtons. Percent difference in pullout strength between the partially threaded cancellous screw and threaded K-wire diminished with increased depth of insertion and increased foam density. Offset axial load to initiate fracture displacement in a synthetic tibia model averaged 1540+/-138 Newtons for the partially threaded cancellous screws, 1,318+/-117 Newtons for the threaded K-wires, and 1,287+/-121 Newtons for the smooth K-wires (p > 0.05). Average time of fixation of a medial malleolar fragment by orthopedic surgeons with a variety of experience levels in a synthetic tibia with two threaded K-wires (114+/-8 seconds) was significantly faster (p < 0.05) than with two partially threaded cancellous screws (207+/-20 seconds). CONCLUSIONS: Threaded K-wires show substantial pullout strength and similar resistance to offset axial load when compared with partially threaded cancellous screws. These threaded K-wires offer an alternative for the internal fixation of medial malleolus fractures.
Bone Screws↗