IMMAN : an R/Bioconductor package for Interolog protein network reconstruction, mapping and mining analysis

Background: Reconstruction of protein-protein interaction networks (PPIN) has been riddled with controversy for decades. Particularly, false-negative and - positive interactions make this progress even more complicated. Also, lack of a standard PPIN limits us in the comparison studies and results in the incompatible outcomes. Using an evolution-based concept, i.e. interolog which refers to interacting orthologous protein sets, pave the way toward an optimal benchmark. Results: Here, we provide an R package, IMMAN, as a tool for reconstructing Interolog Protein Network (IPN) by integrating several Protein-protein Interaction Networks (PPINs). Users can unify different PPINs to mine conserved common networks among species. IMMAN is designed to retrieve IPNs with different degrees of conservation to engage prediction analysis of protein functions according to their networks. Conclusions: IPN consists of evolutionarily conserved nodes and their related edges regarding low false positive rates, which can be considered as a gold standard network in the contexts of biological network analysis regarding to those PPINs which is derived from.Peer reviewe

Active processes in one dimension

We consider the thermal and athermal overdamped motion of particles in 1D geometries where discrete internal degrees of freedom (spin) are coupled with the translational motion. Adding a driving velocity that depends on the time-dependent spin constitutes the simplest model of active particles (run-and-tumble processes) where the violation of the equipartition principle and of the Sutherland-Einstein relation can be studied in detail even when there is generalized reversibility. We give an example (with four spin values) where the irreversibility of the translational motion manifests itself only in higher-order (than two) time correlations. We derive a generalized telegraph equation as the Smoluchowski equation for the spatial density for an arbitrary number of spin values. We also investigate the Arrhenius exponential law for run-and-tumble particles, due to their activity the slope of the potential becomes important in contrast to the passive diffusion case and activity enhances the escape from a potential well (if that slope is high enough). Finally, in the absence of a driving velocity, the presence of internal currents such as in the chemistry of molecular motors may be transmitted to the translational motion and the internal activity is crucial for the direction of the emerging spatial current.Comment: 26 pages, 3 figure

The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98 -rearranged AML

Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin–MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL–Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation

Effect of screw access hole preparation on fracture load of implant-supported zirconia-based crowns: an in vitro study

Background. Fracture load of implant-supported restorations is an important factor in clinical success. This study evaluated the effect of two techniques for screw access hole preparation on the fracture load of cement-screw-retained implant-supported zirconia-based crowns. Methods. Thirty similar cement-screw-retained implant-supported zirconia-based maxillary central incisor crowns were evaluated in three groups of 10. Group NH: with no screw access holes for the control; Group HBS: with screw access holes prepared with a machine before zirconia sintering; Group HAS: with screw access holes prepared manually after zirconia sintering. In group HBS, the access holes were virtually designed and prepared by a computer-assisted design/computer-assisted manufacturing system. In group HAS, the access holes were manually prepared after zirconia sintering using a diamond bur. The dimensions of the screw access holes were equal in both groups. The crowns were cemented onto same-size abutments and were then subjected to thermocycling. The fracture load values of the crowns were measured using a universal testing machine. Data were analyzed with ANOVA and Tukey test (P < 0.05). Results. The mean fracture load value for the group NH was 888.37 ± 228.92 N, which was the highest among the groups, with a significant difference (P < 0.0001). The fracture load values were 610.48 ± 125.02 N and 496.74 ± 104.10 Nin the HBS and HAS groups, respectively, with no significant differences (P = 0.44). Conclusion. Both techniques used for preparation of screw access holes in implant-supported zirconia-based crowns de-creased the fracture load

Prophylactic Antibiotics in Otolaryngologic Surgeries: From Knowledge to Practice

Introduction: The management and use of antimicrobial drugs has clinical, economic, and environmental implications. In many countries, antimicrobial drugs are the most frequently prescribed therapeutic agents. Therefore, health-care policy should focus on how to establish a rational attitude toward antibiotics. This study was performed to investigate antibiotic usage as a prophylactic regimen in head and neck surgeries.  Materials and Methods: This study was a retrospective case series. Patients undergoing otolaryngology surgeries in a tertiary referral otolaryngology center were included. Members of operating room staff that were unaware of the study objectives collected patients’ data using a questionnaire that contained information regarding general medical condition, disease, surgical procedure, and prophylaxis regimen and duration.   Results: Excluding infected patients, we studied 1349 patients during a four-month period who needed prophylactic antibiotics. A total of 34 different types of surgical procedures were performed. Out of the total number of patients, 503 (37.0%) received a parenteral antibiotic directly before surgery. The main antibiotics used before surgery were cephalosporins (94.9%). All of the 1349 patients were administered antibiotics after the procedure. These antibiotics where given with a mean number of doses of 4.81 (range: 1–68), and also consisted of mostly cephalosporins. Conclusion: Our results indicate that prophylactic antibiotics were being significantly misused in a tertiary referral center of a university hospital. Although teaching the principles of prophylaxis to physicians is important, we think that finding a way to bring this knowledge to practice is more important

Nanoparticle-mediated targeting of the fusion gene RUNX1/ETO in t(8;21)-positive acute myeloid leukaemia

A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBFβ. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies

Additional file 6: of A systematic survey of centrality measures for protein-protein interaction networks

Clustering properties results. These properties include connectivity, Dunn and Silhouette scores. These scores suggest the sufficient clustering method by a specific number of clusters. (DOCX 16 kb