DNA end resection by Dna2–Sgs1–RPA and its stimulation by Top3–Rmi1 and Mre11–Rad50–Xrs2

The repair of DNA double-strand breaks (DSBs) by homologous recombination requires processing of broken ends. For repair to start, the DSB must first be resected to generate a 3′-single-stranded DNA (ssDNA) overhang, which becomes a substrate for the DNA strand exchange protein, Rad51 (ref. 1). Genetic studies have implicated a multitude of proteins in the process, including helicases, nucleases and topoisomerases. Here we biochemically reconstitute elements of the resection process and reveal that it requires the nuclease Dna2, the RecQ-family helicase Sgs1 and the ssDNA-binding protein replication protein-A (RPA). We establish that Dna2, Sgs1 and RPA constitute a minimal protein complex capable of DNA resection in vitro. Sgs1 helicase unwinds the DNA to produce an intermediate that is digested by Dna2, and RPA stimulates DNA unwinding by Sgs1 in a species-specific manner. Interestingly, RPA is also required both to direct Dna2 nucleolytic activity to the 5′-terminated strand of the DNA break and to inhibit 3′ to 5′ degradation by Dna2, actions that generate and protect the 3′-ssDNA overhang, respectively. In addition to this core machinery, we establish that both the topoisomerase 3 (Top3) and Rmi1 complex and the Mre11–Rad50–Xrs2 complex (MRX) have important roles as stimulatory components. Stimulation of end resection by the Top3–Rmi1 heterodimer and the MRX proteins is by complex formation with Sgs1 (refs 5, 6), which unexpectedly stimulates DNA unwinding. We suggest that Top3–Rmi1 and MRX are important for recruitment of the Sgs1–Dna2 complex to DSBs. Our experiments provide a mechanistic framework for understanding the initial steps of recombinational DNA repair in eukaryotes

Flavour physics constraints in the BMSSM

We study the implications of the presence of the two leading-order, non-renormalizable operators in the Higgs sector of the MSSM to flavour physics observables. We identify the constraints of flavour physics on the parameters of the BMSSM when we: a) focus on a region of parameters for which electroweak baryogenesis is feasible, b) use a CMSSM-like parametrization, and c) consider the case of a generic NUHM-type model. We find significant differences as compared to the standard MSSM case.Comment: 22 pages, 7 figure

Antimony-doped graphene nanoplatelets

Heteroatom doping into the graphitic frameworks have been intensively studied for the development of metal-free electrocatalysts. However, the choice of heteroatoms is limited to non-metallic elements and heteroatom-doped graphitic materials do not satisfy commercial demands in terms of cost and stability. Here we realize doping semimetal antimony (Sb) at the edges of graphene nanoplatelets (GnPs) via a simple mechanochemical reaction between pristine graphite and solid Sb. The covalent bonding of the metalloid Sb with the graphitic carbon is visualized using atomic-resolution transmission electron microscopy. The Sb-doped GnPs display zero loss of electrocatalytic activity for oxygen reduction reaction even after 100,000 cycles. Density functional theory calculations indicate that the multiple oxidation states (Sb3+ and Sb5+) of Sb are responsible for the unusual electrochemical stability. Sb-doped GnPs may provide new insights and practical methods for designing stable carbon-based electrocatalystsclose0

Fine Tuning in General Gauge Mediation

We study the fine-tuning problem in the context of general gauge mediation. Numerical analyses toward for relaxing fine-tuning are presented. We analyse the problem in typical three cases of the messenger scale, that is, GUT ($2\times10^{16}$ GeV), intermediate ($10^{10}$ GeV), and relatively low energy ($10^6$ GeV) scales. In each messenger scale, the parameter space reducing the degree of tuning as around 10% is found. Certain ratios among gluino mass, wino mass and soft scalar masses are favorable. It is shown that the favorable region becomes narrow as the messenger scale becomes lower, and tachyonic initial conditions of stop masses at the messenger scale are favored to relax the fine-tuning problem for the relatively low energy messenger scale. Our spectra would also be important from the viewpoint of the $\mu-B$ problem.Comment: 22 pages, 16 figures, comment adde

Short-wavelength infrared photodetector on Si employing strain-induced growth of very tall InAs nanowire arrays

One-dimensional crystal growth enables the epitaxial integration of III-V compound semiconductors onto a silicon (Si) substrate despite significant lattice mismatch. Here, we report a short-wavelength infrared (SWIR, 1.4-3 mu m) photodetector that employs InAs nanowires (NWs) grown on Si. The wafer-scale epitaxial InAs NWs form on the Si substrate without a metal catalyst or pattern assistance; thus, the growth is free of metal-atom-induced contaminations, and is also cost-effective. InAs NW arrays with an average height of 50 mu m provide excellent anti-reflective and light trapping properties over a wide wavelength range. The photodetector exhibits a peak detectivity of 1.9 x 10(8) cm.Hz(1/2)/W for the SWIR band at 77 K and operates at temperatures as high as 220 K. The SWIR photodetector on the Si platform demonstrated in this study is promising for future low-cost optical sensors and Si photonicsopen0

Protein C anticoagulant system—anti-inflammatory effects

Activated protein C (APC) plays active roles in preventing progression of a number of disease processes. These include thrombosis due to its direct anticoagulant activity which is likely augmented by its cytoprotective activity, thereby limiting exposure of procoagulant cellular membrane surfaces on cells. Beyond that, the pathway signals the cells to prevent apoptosis, to dampen inflammation, to increase endothelial barrier function, and to selectively downregulate some genes implicated in disease progression. Most of these functions are manifested to APC binding to endothelial protein C receptor (EPCR) allowing PAR1 activation, but activation of other PARS is also implicated in some cases. In addition to EPCR orchestrating these changes, CD11b is also capable of supporting APC signaling. Selective control of these pathways offers potential in new therapeutic approaches to disease

Symptomatic snapping knee from biceps femoris tendon subluxation: an unusual case of lateral pain in a marathon runner

Snapping biceps femoris syndrome is an uncommon cause of lateral knee pain and may be difficult to diagnose, resulting in unsuccessful surgical intervention. In this report, we present an unusual case of a 37-year-old male marathon runner with unilateral snapping knee secondary to dislocation of the long head of the biceps femoris over the fibular head during knee flexion. The pain was great enough to interfere with his ability to practice sport. Possible causes of symptomatic snapping knee include multiple intra-articular or extra-articular pathology. Biceps femoris snapping over the fibular head is a rare condition. Reported causes include an anomalous insertion of the tendon into the tibia, trauma, and fibular-head abnormality. However, none of those conditions accounted for his symptoms. Failing conservative treatment, the patient underwent surgery for partial resection of the fibular head, with subsequent sudden resolution of symptoms and return to sport. Accurate knowledge and management of this rare condition is mandatory to avoid inappropriate therapy and unnecessary surgical procedures

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Improved Surgical Outcomes for Breast Cancer Patients Receiving Neoadjuvant Aromatase Inhibitor Therapy: Results from a Multicenter Phase II Trial

Background: Neoadjuvant aromatase inhibitor therapy has been reported to improve surgical outcomes for postmenopausal women with clinical stage II or III hormone receptor-positive breast cancer. A multicenter phase II clinical trial was conducted to investigate the value of this approach for US surgical practice. Study Design: One hundred fifteen postmenopausal women with >2 cm, estrogen receptor (ER) or progesterone receptor (PgR)-positive breast cancer were enrolled in a trial of 16 to 24 weeks of letrozole 2.5 mg daily before operation. Results: One hundred six patients were eligible for primary analysis, 96 underwent operations, 7 received chemotherapy after progressive disease, and 3 did not undergo an operation. Baseline surgical status was marginal for breast-conserving surgery (BCS) in 48 (45%), 47 were definitely ineligible for BCS (44%), and 11 were inoperable by standard mastectomy (10%). Overall Response Evaluation Criteria In Solid Tumors clinical response rate in the breast was 62%, with 12% experiencing progressive disease. Fifty percent underwent BCS, including 30 of 46 (65%) patients who were initially marginal for BCS and 15 of 39 (38%) patients who were initially ineligible for BCS. All 11 inoperable patients successfully underwent operations, including 3 (27%) who had BCS. Nineteen percent of patients undergoing mastectomy had a pathologic T1 tumor, suggesting that some highly responsive tumors were overtreated surgically. Conclusions: Neoadjuvant aromatase inhibitor improves operability and facilitates BCS, but there was considerable variability in responsiveness. Better techniques to predict response, determine residual tumor burden before operation, and greater willingness to attempt BCS in responsive patients could additionally improve the rate of successful BCS