Notes

S2L-PSIBLAST: any supervised two-layer research framework based on PSI-BLAST for health proteins remote control homology recognition.
The recently developed magnetically controlled growing rod (MCGR) system has gained popularity because it limits additional surgical lengthening procedures and promises reduction of the complication rate previously reported for the traditional growing rods. A retrospective single-center study was performed. Demographic and complications data were recorded. A statistical analysis was conducted to quantify the effect of MCGR placement and of subsequent lengthening on the Cobb angle, T1-T12 kyphosis, and the distances from T1-T12 and T1-S1. Twenty-four patients met the inclusion criteria. Six had idiopathic scoliosis and 18 patients had nonidiopathic scoliosis (neuromuscular and syndromic scoliosis). Nine patients underwent primary MCGR placement, and 15 had the traditional growing rods removed and replaced with MCGRs. The mean age at surgery and at last follow-up was 6.3 years and 8.8 years, respectively. The mean follow-up was 29.2 months. The MCGR placement significantly reduced the Cobb angle and kyphosis by an average of 21.33° and 10.79°, respectively. The T1-T12 and the T1-S1 distances increased an average of 1.19 and 1.89 cm/year, respectively, during the follow-up period. The average percentage of achieved-to-intended distraction was 65% on the concave side and 68% on the convex side at last follow-up. There were 9 postoperative complications in 8 (33%) patients, 6 of whom had nonidiopathic scoliosis. The MCGR system is reliable and effective in the treatment of patients affected by early-onset scoliosis. [Orthopedics. 2020;43(6)e601-e608.].The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) is a metric for patient satisfaction consisting of 19 questions divided into 10 domains. Scores affect hospital reimbursements and accreditation and may play a role in patient outcomes. It is unclear how length of stay and other factors affect each of the 10 domains. This retrospective review gathered data of 600 patients between December 2008 and January 2017 who completed the HCAHPS survey. The odds of complete satisfaction in each of the 10 domains was evaluated. The results suggest increased length of stay is associated with lower odds of patient satisfaction and decreased likelihood of recommending the hospital. The odds of being completely satisfied regarding communication with physicians, discharge information, and responsiveness of the hospital staff, as well as the odds of recommending the hospital to others, were lower if the care provider was younger than the patient. Obese patients were also more likely to be satisfied with responsiveness and care transition. Male patients were more satisfied with communication about medications (odds ratio [OR], 1.694), care transition (OR, 1.489), and cleanliness (OR, 2.120). Medicare and fewer consults were related to increased odds of patient satisfaction with care transition (OR, 1.748 and 0.573, respectively). Males, older patients, and White patients were more likely to recommend the hospital (OR, 1.476, 1.025, and 1.690, respectively). Length of stay affects patient satisfaction and likelihood of recommending the hospital to others. Other factors such as a younger provider age than the patient, lower body mass index, female sex, non-Medicare insurance, and higher number of consults are also associated with lower satisfaction in various domains. Hospital systems can bolster patient satisfaction by strategizing day-of-surgery and weekend staffing to reduce length of stay. [Orthopedics. 2020;43(6)373-379.].Few studies report on periprosthetic humeral shaft fractures after reverse total shoulder arthroplasty (RTSA). The authors evaluated outcomes of 5 patients with this complication who were initially treated nonoperatively. Of 152 patients who underwent RTSA at the authors' institution from 2012 to 2017, 4 experienced periprosthetic humeral shaft fractures. One patient was referred to the authors for fracture treatment. All 5 patients were initially treated nonoperatively. The mean duration of follow-up was 11.5 months (range, 1.5-26 months). The authors analyzed time to fracture union, Single Assessment Numeric Evaluation (SANE) score, visual analog scale (VAS) score for pain, and active shoulder range of motion. Fracture union occurred in 4 patients treated nonoperatively at a mean of 4.4 months. Mean SANE score was 55 of 100 (range, 20-85). Mean VAS score was 3.4 of 10 (range, 0-8). Mean forward elevation was 83° (range, 45°-110°); mean abduction was 65° (range, 45°-80°); and mean external rotation with the arm at the side was 15° (range, 0°-30°). Many factors must be considered when customizing treatment for patients with periprosthetic fracture after RTSA. This case series indicates that nonoperative treatment of postoperative periprosthetic humeral shaft fractures can be successful. [Orthopedics. 2020;43(6)e553-e560.].Endosymbiosis with chemosynthetic bacteria has enabled many deep-sea invertebrates to thrive at hydrothermal vents and cold seeps, but most previous studies on this mutualism have focused on the bacteria only. Transmembrane Transporters inhibitor Vesicomyid clams dominate global deep-sea chemosynthesis-based ecosystems. They differ from most deep-sea symbiotic animals in passing their symbionts from parent to offspring, enabling intricate coevolution between the host and the symbiont. Here, we sequenced the genomes of the clam Archivesica marissinica (Bivalvia Vesicomyidae) and its bacterial symbiont to understand the genomic/metabolic integration behind this symbiosis. At 1.52 Gb, the clam genome encodes 28 genes horizontally transferred from bacteria, a large number of pseudogenes and transposable elements whose massive expansion corresponded to the timing of the rise and subsequent divergence of symbiont-bearing vesicomyids. The genome exhibits gene family expansion in cellular processes that likely facilitate chemoautotrophy, including gas delivery to support energy and carbon production, metabolite exchange with the symbiont, and regulation of the bacteriocyte population. Contraction in cellulase genes is likely adaptive to the shift from phytoplankton-derived to bacteria-based food. It also shows contraction in bacterial recognition gene families, indicative of suppressed immune response to the endosymbiont. The gammaproteobacterium endosymbiont has a reduced genome of 1.03 Mb but retains complete pathways for sulfur oxidation, carbon fixation, and biosynthesis of 20 common amino acids, indicating the host's high dependence on the symbiont for nutrition. Overall, the host-symbiont genomes show not only tight metabolic complementarity but also distinct signatures of coevolution allowing the vesicomyids to thrive in chemosynthesis-based ecosystems.Increasing fetal hemoglobin (HbF) provides clinical benefit in patients with sickle cell disease (SCD). We recently identified heme-regulated inhibitor (HRI, EIF2AK1), as a novel HbF regulator. Because HRI is an erythroid-specific protein kinase, it presents a potential target for pharmacologic intervention. We found that maximal HbF induction required >80% to 85% HRI depletion. Because it remains unclear whether this degree of HRI inhibition can be achieved pharmacologically, we explored whether HRI knockdown can be combined with pharmacologic HbF inducers to achieve greater HbF production and minimize potential adverse effects associated with treatments. Strongly cooperative HbF induction was observed when HRI depletion was combined with exposure to pomalidomide or the EHMT1/2 inhibitor UNC0638, but not to hydroxyurea. Mechanistically, reduction in the levels of the HbF repressor BCL11A reflected the cooperativity of HRI loss and pomalidomide treatment, whereas UNC0638 did not modulate BCL11A levels. In conjunction with HRI loss, pomalidomide maintained its HbF-inducing activity at 10-fold lower concentrations, in which condition there were minimal observed detrimental effects on erythroid cell maturation and viability, as well as fewer alterations in the erythroid transcriptome. When tested in cells from patients with SCD, combining HRI depletion with pomalidomide or UNC0638 achieved up to 50% to 60% HbF and 45% to 50% HbF, respectively, as measured by high-performance liquid chromatography, and markedly counteracted cell sickling. In summary, this study provides a foundation for the exploration of combining future small-molecule HRI inhibitors with additional pharmacologic HbF inducers to maximize HbF production and preserve erythroid cell functionality for the treatment of SCD and other hemoglobinopathies.B-cell maturation antigen (BCMA), a member of the tumor necrosis factor family of receptors, is predominantly expressed on the surface of terminally differentiated B cells. BCMA is highly expressed on plasmablasts and plasma cells from multiple myeloma (MM) patient samples. We developed a BCMAxCD3 bispecific antibody (teclistamab [JNJ-64007957]) to recruit and activate T cells to kill BCMA-expressing MM cells. Teclistamab induced cytotoxicity of BCMA+ MM cell lines in vitro (H929 cells, 50% effective concentration [EC50] = 0.15 nM; MM.1R cells, EC50 = 0.06 nM; RPMI 8226 cells, EC50 = 0.45 nM) with concomitant T-cell activation (H929 cells, EC50 = 0.21 nM; MM.1R cells, EC50 = 0.1 nM; RPMI 8226 cells, EC50 = 0.28 nM) and cytokine release. This activity was further increased in the presence of a γ-secretase inhibitor (LY-411575). Teclistamab also depleted BCMA+ cells in bone marrow samples from MM patients in an ex vivo assay with an average EC50 value of 1.7 nM. Under more physiological conditions using healthy human whole blood, teclistamab mediated dose-dependent lysis of H929 cells and activation of T cells. Antitumor activity of teclistamab was also observed in 2 BCMA+ MM murine xenograft models inoculated with human T cells (tumor inhibition with H929 model and tumor regression with the RPMI 8226 model) compared with vehicle and antibody controls. The specific and potent activity of teclistamab against BCMA-expressing cells from MM cell lines, patient samples, and MM xenograft models warrant further evaluation of this bispecific antibody for the treatment of MM. Phase 1 clinical trials (monotherapy, #NCT03145181; combination therapy, #NCT04108195) are ongoing for patients with relapsed/refractory MM.The SH2-JH2 linker domain of JAK2 has been implicated in the negative regulation of JAK2 activity. In 2 patients with myeloproliferative neoplasms (MPNs), we identified and characterized the novel JAK2 mutation S523L, which occurs in a key residue in the linker region. In 1 case, acquisition of JAK2S523L was associated with thrombocytosis and bone marrow megakaryocytic hyperplasia, and there were no other somatic alterations in this patient. The second patient with JAK2S523Lmutation presented with increased hematocrit and had concurrent mutations in RUNX1 and BCORL1. Consistent with the genetic and clinical data, expression of JAK2S523L causes interleukin-3-independent growth in Ba/F3 cells transduced with the erythropoietin receptor by constitutively active Jak2/Stat5 signaling.
Current techniques of protein engineering focus mostly on re-designing small targeted regions or defined structural scaffolds rather than constructing combinatorial libraries of versatile compositions and lengths. This is a missed opportunity because combinatorial libraries are emerging as a vital source of novel functional proteins and are of interest in diverse research areas.

Here, we present a computational tool for Combinatorial Library Design (CoLiDe) offering precise control over protein sequence composition, length and diversity. The algorithm uses evolutionary approach to provide solutions to combinatorial libraries of degenerate DNA templates. We demonstrate its performance and precision using 4 different input alphabet distribution on different sequence lengths. In addition, a model design and experimental pipeline for protein library expression and purification is presented, providing a proof-of-concept that our protocol can be used to prepare purified protein library samples of up to 1011-1012 unique sequences.
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