Miracle-dz/UniFAR-FTUs huggingface dataset:
Crystal Structure of a Conformation-selective Casein Kinase-1 Inhibitor*

Members of the casein kinase-1 family of protein kinases play an essential role in cell regulation and disease pathogenesis. Unlike most protein kinases, they appear to function as constitutively active enzymes. As a result, selective pharmacological inhibitors can play an important role in dissection of casein kinase-1-dependent processes. To address this need, new small molecule inhibitors of casein kinase-1 acting through ATP-competitive and ATP-noncompetitive mechanisms were isolated on the basis of in vitro screening. Here we report the crystal structure of 3-[(2,4,6-trimethoxyphenyl) methylidenyl]-indolin-2-one (IC261), an ATP-competitive inhibitor with differential activity among casein kinase-1 isoforms, in complex with the catalytic domain of fission yeast casein kinase-1 refined to a crystallographicR-factor of 22.4% at 2.8 Å resolution. The structure reveals that IC261 stabilizes casein kinase-1 in a conformation midway between nucleotide substrate liganded and nonliganded conformations. We propose that adoption of this conformation by casein kinase-1 family members stabilizes a delocalized network of side chain interactions and results in a decreased dissociation rate of inhibitor.
A Novel Buck–Boost AC–AC Converter With Both Inverting and Noninverting Operations and Without Commutation Problem

This paper proposes a new type of ac-ac converter which can operate as traditional noninverting buck and boost converters, and inverting buck-boost converter as well. The proposed converter uses six unidirectional current flowing and bidirectional voltage blocking switches, implemented by six reverse blocking insulated-gate bipolar transistors (IGBTs) or series mosfet-diode pairs, two input and output filter capacitors, and one inductor. It has no shoot-through problem of voltage source (or capacitor) even when all switches are turned-on, and therefore, pulsewidth modulation dead-times are not needed resulting in high-quality waveforms, and solves the commutation problem without using bulky and lossy RC snubbers or dedicated soft-commutation strategies. It has smaller switching losses because only two switches out of six are switched at high frequency during each half-cycle of input voltage, and it can use power MOSFETs as body diode never conducts, making it immune from mosfet failure risk which otherwise may occur due to poor reverse recovery problem of body diode. The noninverting buck-boost mode of the proposed converter can be used in applications with both step-up and step-down demand, while the inverting buck-boost mode can also be used in its application as dynamic voltage restorer. Detailed analysis of the proposed converter is given, and experimental results are also provided.
Similar Intracellular Peptide Profile of TAP1/β2 Microglobulin Double-Knockout Mice and C57BL/6 Wild-Type Mice as Revealed by Peptidomic Analysis

Cells produce and use peptides in distinctive ways. In the present report, using isotope labeling plus semi-quantitative mass spectrometry, we evaluated the intracellular peptide profile of TAP1/β2m−/− (transporter associated with antigen-processing 1/ß2 microglobulin) double-knockout mice and compared it with that of C57BL/6 wild-type animals. Overall, 92 distinctive peptides were identified, and most were shown to have a similar concentration in both mouse strains. However, some peptides showed a modest increase or decrease (~2-fold), whereas a glycine-rich peptide derived from the C-terminal of neurogranin (KGPGPGGPGGAGGARGGAGGGPSGD) showed a substantial increase (6-fold) in TAP1/β2m−/− mice. Thus, TAP1 and β2microglobulin have a small influence on the peptide profile of neuronal tissue, suggesting that the presence of peptides derived from intracellular proteins in neuronal tissue is not associated with antigens of the class I major histocompatibility complex. Therefore, it is possible that these intracellular peptides play a physiological role.
p53 Monitors Replication Fork Regression by Binding to “Chickenfoot” Intermediates*

The tumor suppressor protein, p53, utilizes multiple mechanisms to ensure faithful transmission of the genome including regulation of DNA replication, repair, and recombination. Monitoring these pathways may involve direct binding of p53 to the DNA intermediates of these processes. In this study, we generated templates resembling stalled replication forks and utilized electron microscopy to examine p53 interactions with these substrates. Our results show that p53 bound with high affinity to the junction of stalled forks, whereas two cancer-derived p53 mutants showed weak binding. Additionally, some of the templates were rearranged to form “chickenfoot” structures in the presence of p53. These were mostly formed due to p53 trapping intermediates of spontaneous fork regression; however, in a small population, the protein appeared to be promoting their formation. Collectively, these results demonstrate the importance of sequence-independent binding in p53-mediated maintenance of genomic integrity.
A Robust Correlation Method for Solving Permutation Problem in Frequency Domain Blind Source Separation of Speech Signals

This paper addresses the well-known permutation problem, inconsistent permutation in the discrete Fourier transform bins after independent component analysis, in the frequency domain blind source separation. The method which utilizes the correlation between the adjacent bins in speech signals is popular among the techniques for solving permutation problem. However, the reliability of the method is very low. This paper presents a robust correlation method for solving the permutation problem, which utilizes the correlation between the signals in each DFT bin, one of which is partially separated by a time domain BSS method and the other is obtained by a frequency domain BSS method. The proposed method showed almost the same separation performance as that of the method which uses the correlation between adjacent bins and is highly reliable at the same time
Integrated Patient Coordination System (IntPaCS): a bespoke tool for surgical patient management

Background Efficient handover of patient information is fundamental for patient care and service efficiency. An audit exploring surgeons’ views on written handover within a Trust's surgical specialties concluded that clear deficiencies existed. Such concerns have been echoed in the General Medical Council's guidance on safe surgical handover. Aims To design and implement bespoke software for surgical handover using the audit results of surgeons’ perceptions of existing processes. To gain feedback from the surgical department on this new software and implement a long-term sustainability strategy. Methods Following an initial review, a proposal was presented for a new patient management tool. The software was designed and developed in-house to reflect the needs of our surgeons. The bespoke programme used open-source coding and was maintained on a secure server. A review of surgical handover occurred 12 and 134 weeks post-implementation of the new software. Results Integrated Patient Coordination System (IntPaCS) was successfully developed and delivered. The system is a centralised platform that enables the visualisation, handover and audit/research of surgical inpatient information in any part of the hospital. Feedback found that clinicians found it less stressful to create a post-take handover (60% vs 36%) than using a Word document. IntPaCS was found to be quicker to use too (15 min (SD 4) vs 24 min (SD 7.5)). Finally, the new system was considered safer with less reported missing/incorrect patient data (48% vs 9%). Conclusions This study has shown that careful use of emerging technology and innovation over time has the potential to improve all aspects of clinical governance.
California Curriculum Policy in the 1990's: "We Don't Have To Be in Front To Lead.".

This case study traces the evolution of curriculum-related' educational reforms in California, concentrating on those that have influenced mathematics and science. These reform efforts are examined in the framework of the state's political and policy context. Data came from interviews, a synthesis of the research literature, and newspaper accounts of events. Over 20 people were interviewed to describe the evolution of curriculum and policy. For more than a decade, California has been considered a leader in curriculum reform, and by the 1990s, the state had developed frameworks in all core subject areas. These frameworks passed through several versions, with particular controversy associated with the language arts framework. The language arts framework was not associated with improved reading achievement and was characterized in the public mind as an expensive experiment. Similar concerns were expressed about the mathematics framework, but science reform has largely stayed out of the limelight of controversy. Parallel to the backlash to the frameworks has been a backlash to performance-based assessment in California, as evidenced by the dissatisfaction with the California Learning Assessment System. Public concerns about professional development and other educational policies have also threatened the promising start California made in the 1980s. Political changes have splintered state leadership and policy direction, until the comprehensive curriculum-driven reform movement is at a crossroads. (Contains 35 references.) (SLD) ******************************************************************************** Reproductions supplied by EDRS are the best that can be made from the original document. ******************************************************************************** CALIFORNIA CURRICULUM POLICY IN THE 1990' s: "WE DON'T HAVE TO BE IN FRONT TO LEAD" U.S. DEPARTMENT OF EDUCATION Office of Educational Research and Improvement EDUC TIONAL RESOURCES INFORMATION CENTER (ERIC) This document has been reproduced as received from the person or organization originating it. 0 Minor changes have been made to improve reproduction quality. Points of view or opinions stated in this document do not necessarily represent official OERI position or policy. by Lisa Carlos Policy Support and Studies WestEd, San Francisco
Heterogeneity in F‐actin polymerization of cord blood polymorphonuclear leukocytes stimulated by N‐formyl‐ methionyl‐leucyl‐phenylalanine

Abstract Background: To elucidate the mechanism responsible for defects of polymorphonuclear leukocyte (PMNL) chemotaxis of neonates, we determined actin polymerization of NBD (7‐nitrobenz‐2‐oxa‐diazol)‐phallacidin‐stained PMNL following stimulation with either N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP) or phorbol myristate acetate (PMA) in cord blood and adult controls.
Prevalence of cervical insufficiency in polycystic ovarian syndrome.

BACKGROUND Pregnant women with polycystic ovarian syndrome (PCOS) experience a greater rate of adverse obstetrical outcomes compared with non-PCOS women. We examined the prevalence and incidence of cervical insufficiency (CI) in a community cohort of pregnant women with and without PCOS. METHODS A retrospective cohort study was conducted within a large integrated health care delivery system among non-diabetic PCOS women with second or third trimester delivery during 2002-2005 (singleton or twin gestation). PCOS was defined by Rotterdam criteria. A non-PCOS comparison group matched for delivery year and hospital facility was used to estimate the background rate of CI. Women were designated as having new CI diagnosed in the index pregnancy (based on cervical dilation and/or cervical shortening) and prior CI based on prior diagnosis of CI with prophylactic cerclage placed in the subsequent pregnancy. RESULTS We identified 999 PCOS women, of whom 29 (2.9%) had CI. There were 18 patients with new CI and 11 with prior CI having prophylactic cerclage placement; four CI patients had twin gestation. In contrast, only five (0.5%) non-PCOS women had CI: two with new CI and three with prior CI. The proportion of newly diagnosed incident CI (1.8 versus 0.2%) or prevalent CI (2.9 versus 0.5%) was significantly greater for PCOS compared with non-PCOS pregnant women (both P < 0.01). Among PCOS women, CI prevalence was particularly high among South Asians (7.8%) and Blacks (17.5%) compared with Whites (1%) and significantly associated with gonadotropin use (including in vitro fertilization). Overall, the PCOS status was associated with an increased odds of prevalent CI pregnancy (adjusted odds ratio 4.8, 95% confidence interval 1.5-15.4), even after adjusting for maternal age, nulliparity, race/ethnicity, body mass index and fertility treatment. CONCLUSION In this large and ethnically diverse PCOS cohort, we found that CI occurred with a higher than expected frequency in PCOS women, particularly among South Asian and Black women. PCOS women with CI were also more likely to have received gonadotropin therapy. Future studies should examine whether natural and hormone-altered PCOS is a risk factor for CI, the role of race/ethnicity, fertility drugs and consideration for heightened mid-trimester surveillance in higher risk subgroups of pregnant women with PCOS.
Potential Nectin-1 Binding Site on Herpes Simplex Virus Glycoprotein D

ABSTRACT Four glycoproteins (gD, gB, gH, and gL) are essential for herpes simplex virus (HSV) entry into cells. An early step of fusion requires gD to bind one of several receptors, such as nectin-1 or herpesvirus entry mediator (HVEM). We hypothesize that a conformational change in gD occurs upon receptor binding that triggers the other glycoproteins to mediate fusion. Comparison of the crystal structures of gD alone and gD bound to HVEM reveals that upon HVEM binding, the gD N terminus transitions from a flexible stretch of residues to a hairpin loop. To address the contribution of this transition to the ability of gD to trigger fusion, we attempted to “lock” the gD N terminus into a looped conformation by engineering a disulfide bond at its N and C termini. The resulting mutant (gD-A3C/Y38C) failed to trigger fusion in the absence of receptor, suggesting that formation of the loop is not the sole fusion trigger. Unexpectedly, although gD-A3C/Y38C bound HVEM, it failed to bind nectin-1. This was due to the key role played by Y38 in interacting with nectin-1. Since tyrosines are often “hot spot” residues at the center of protein-protein interfaces, we mutated residues that surround Y38 on the same face of gD and tested their binding and functional properties. Our results suggest that this region of gD is important for nectin-1 interaction and is distinct from but partially overlaps the site of HVEM binding. Unique gD mutants with altered receptor usage generated in this study may help dissect the roles played by various HSV receptors during infection.
Effect of mutations in the small envelope protein of hepatitis B virus on assembly and secretion of hepatitis delta virus.

The gene coding for the small (S) envelope protein of hepatitis B virus was mutated to identify sequences important for the envelopment of the nucleocapsid during morphogenesis of hepatitis delta virus (HDV) virions. This study was focused on a domain of the S protein that is exposed in the cytoplasm during synthesis and thereby represented a good candidate for interaction with the viral nucleocapsid during virion assembly. The mutations consisted of deletion/insertions spanning the entire cytosolic domain of S between amino acid residues 24 and 80. Although the expression of mutants clustered between residues 59 and 80 could not be obtained, we demonstrated that a large part of the cytosolic loop, from residues 29-47 and 49-59, does not contain motifs essential for production of hepatitis B virus subviral particles or HDV virions. However, deletion of residues 24-28 led to the synthesis of S protein mutant, which was competent for secretion of subviral particles but deficient for production of HDV. We concluded that the sequence between Arg-24 and Ile-28 located at the carboxyl boundary of the transmembrane signal I for S contains residue or residues important for HDV particle assembly.
The Role of Public and Private Insurance in Reducing Losses from Extreme Weather Events and Disasters

This paper describes the challenges victims, insurers and governments face in dealing with insurance for low-probability high-consequence events in both developed and developing economies. In developed economies, given their limited experience with catastrophes, there is a tendency for all three parties to engage in short-term intuitive thinking rather than long-term deliberative thinking when making insurance-related decisions. Here, public-private partnerships can encourage investment in protective measures prior to a disaster, deal with affordability problems and provide coverage for catastrophic risks. Insurance premiums based on risk provide signals to residents and business as to the hazards they face and enable insurers to lower premiums for properties where steps have been taken to reduce their risk. To address issues of equity and fairness, homeowners who cannot afford insurance could be given vouchers tied to loans for investing in loss reduction measures. The National Flood Insurance Program provides an opportunity to implement a public-private partnership that could eventually be extended to other extreme events, while the United Kingdom’s Flood Re provides a good case study. In developing economies, insurance penetration is historically very low. This requires innovative solutions to catastrophic risk insurance such as risk pooling, parametric insurance and micro insurance. Nevertheless, the uninsured and uncompensated losses of disasters remain extensive implying the need for public-private partnerships.
Outcomes Are Poor after Treatment of Sepsis in the Rheumatoid Shoulder

Currently, there is little information regarding treatment of shoulder sepsis in patients with rheumatoid arthritis. This study examines the prognosis and outcome after operative treatment of native shoulder infection in patients with rheumatoid arthritis. Seventeen patients were retrospectively reviewed (20 shoulders) after surgical intervention for shoulder sepsis between 1982 and 2002. Nine patients (12 shoulders) were associated with multiple joint infections. The most common isolated organism from cultures was Staphylococcus aureus in 15 shoulders. Three patients died during initial admission to the hospital (at 7 days, 5 months, and 6 months) because of multisystem organ failure and multiple joint infections. Fourteen patients (15 shoulders) survived for followup, with two excellent, six satisfactory, and seven unsatisfactory results. Mean active elevation was 100°. Further surgery was required in three patients: one synovectomy and two shoulder arthrodeses. In this study, patients with shoulder sepsis with rheumatoid arthritis were found to have a high rate of multiple joint sepsis and unsatisfactory shoulder function. Level of Evidence: Prognostic study, Level IV-2 (case series). See the Guidelines for Authors for a complete description of levels of evidence.
Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models.

BACKGROUND There is a paucity of information about events that follow immediately after tumor cells are triggered to initiate the process of angiogenesis (the formation of new blood vessels). Such information is relevant to the issue of when micrometastases vascularize and has implications for the accessibility of micrometastases to various treatments. In this study, we attempted to monitor events at the initiation of angiogenesis at the earliest possible stage of tumor growth in vivo. METHODS Two different rodent mammary tumor cell lines, R3230Ac from the Fischer 344 rat and 4T1 from the BALB/c mouse, were stably transfected with a gene that encodes an enhanced version of green fluorescence protein (GFP). GFP-labeled R3230Ac or 4T1 cells (about 20-50 cells) were implanted into dorsal skinfold window chambers of Fischer 344 rats or BALB/c mice, respectively. Tumor angiogenesis was then monitored serially and noninvasively for up to 4 weeks. RESULTS Clear evidence of modification of the host vasculature was observed when tumor mass reached approximately 60-80 cells, and functional new blood vessels were seen when tumor mass reached roughly 100-300 cells. Individual tumor cells exhibited a chemotaxis-like growth pattern toward the pre-existing host vasculature. When ex-flk1 (a soluble, truncated vascular endothelial cell growth factor receptor protein known to be antiangiogenic) was injected with the tumor cells, the initial angiogenic and tumor growth activities were inhibited considerably, indicating that angiogenesis inhibitors may halt tumor growth even before the onset of angiogenesis. CONCLUSION Angiogenesis induced by tumor cells after implantation in the host begins at a very early stage, i.e., when the tumor mass contains roughly 100-300 cells. Identification of chemotactic signals that initiate tumor cell migration toward the existing vasculature may provide valuable targets for preventing tumor progression and/or metastases.
Three‐dimensional synaptic ultrastructure in the dentate gyrus and hippocampal area CA3 in the Ts65Dn mouse model of down syndrome

Down syndrome (DS) results from trisomy of human chromosome 21. Ts65Dn mice are an established model for DS and show several phenotypes similar to those in people with DS. However, there is little data on the structural plasticity of synapses in the trisynaptic pathway in the hippocampus. Here we investigate 3D ultrastructure of synapses in the hippocampus of age‐matched control (2N) and Ts65Dn male mice. Serial ultrathin sections and 3D reconstructions characterize synapses in the middle molecular layer (MML) of dentate gyrus and in thorny excrescences (TEs) in proximal portions of apical dendrites of CA3 pyramidal neurons. 3D analysis of synapses shows phenotypes that distinguish Ts65Dn from 2N mice. For the MML, synapse density was reduced by 15% in Ts65Dn vs. 2N mice (P < 0.05). Comparative 3D analyses demonstrate a significant decrease in the number of thorns per TE in CA3 in Ts65Dn vs. 2N mice (by ≈45%, P = 0.01). Individual thorn volume was 3 times smaller in Ts65Dn vs. 2N mice (P = 0.02). A significant decrease in the number of thorn projections per TE in Ts65Dn vs. 2N mice was accompanied by a decrease of filopodium‐like protrusions on the surface of TEs (P = 0.02). However, the volume of postsynaptic densities in CA3 Ts65Dn and 2N mice was unchanged (P = 0.78). Our findings suggest that the high degree of plasticity of CA3 thorns may be connected with their filopodial origin. Alterations of 3D synaptic structure in Ts65Dn mice may further contribute to the diminished plasticity in DS. J. Comp. Neurol. 519:1338–1354, 2011. © 2010 Wiley‐Liss, Inc.