Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumours that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition

Automatic Mode Switching for A Multi-functional Variable Refrigerant Flow System

Multi-functional variable refrigerant flow system (MFVRF) is designed to realize simultaneous heating and cooling for individual zones. It is desirable to use existing measurements to determine switching between different modes under changes of ambient and load conditions, i.e. reversing the mode of indoor unit (IDU) and/or outdoor unit (ODU) heat exchangers (HX), as well as the bumpless transfer for controller switching. In this study, a set of mode switching logic is proposed for a four-zone MFVRF system, which involves both IDU and ODU mode switching actions. For the ODU-HX mode switching, thermodynamic analysis under different load changes reveals the qualitative trend for the air-side and refrigerant-side characteristics as the operation approaches to marginal scenarios. The ODU mode switching is thus based on the air-side temperature difference. Mode switching involving IDU action only is studied with a 1H3C (one heating three cooling) mode, in which IDU-1 is in heating mode and IDU-2, IDU-3 and IDU-4 are in cooling mode. For a given zone load conditions, when the zone temperature of IDU is higher than upper limit of a preset cooling mode hysteresis band, IDU enters the cooling mode by simultaneously opening all related cooling mode valves and closing heating-mode valves within time duration. On the other hand, the cooling mode is turned off by closing all related cooling valves when the zone temperature is lower than the lower limit of the cooling mode temperature band. Similarly, when the zone temperature is lower than lower limit of heating mode temperature band, IDU enters its heating mode. When the zone temperature for IDU is higher than the upper limit of heating mode temperature band, the heating mode is turned off. For ODU Mode Switching, it is proposed in this paper to use the temperature difference between the inlet and outlet air of the ODU HX. To justify the use of ODU air-side temperature differential as the indicator variable for ODU mode switching, several cases of 2H2C (two-heating two-cooling) mode are first simulated, in which the IDU-1 and IDU-2 are operated in heating mode and IDU-3 and IDU-4 are operated in cooling mode. A negative ramp of load change applied to IDU-3 within 1000 seconds. For the ODU-HX, the air inlet temperature is fixed at the ambient 20oC, while the air outlet temperature approaches closer and closer to 20oC under reducing cooling load in IDU-3. Simulation results have revealed the decreasing trend of COP. The T-s diagram for the refrigerant cycle of 2H2C mode is evaluated under several scenarios of reduction in IDU-3 cooling load. It reveals that a decreasing temperature difference at the air side or refrigerant side can be candidate probing variables for mode switching of ODU HX. Also, similar study is conducted when the ODU HX works as evaporator, with the MFVRF system operated in 3H1C (three heating one cooling) mode. Simulations for ODU HX mode switch case have been performed, and the results validate the effectiveness of the proposed scheme of mode switching

Perceptions of knowledge sharing among small family firm leaders: a structural equation model

Small family firms have many unique relational qualities with implications for how knowledge is passed between individuals. Extant literature posits leadership approach as important in explaining differences in knowledge-sharing climate from one firm to another. This study investigates how leadership approaches interact with family influence to inform perceptions of knowledge sharing. We utilize survey data (n = 110) from owner-managers of knowledge-intensive small family firms in Scotland. Our findings present a choice in leadership intention, contrasting organization-focused participation against family-influenced guidance. Insight is offered on the implications of this leadership choice at both organizational and familial level

Distributed Extremum Seeking Control for a Variable Refrigerant Flow System

The variable refrigerant flow (VRF) technology has facilitated the development of multi-split ductless air conditioning systems, in which multiple indoor units (IDU) are used to regulate the refrigerant flow to achieve individualized zoning control. Model based control for VRF system demands for more modeling efforts in part due to diverse configuration, as well as changes in load and ambient conditions. As a model-free control strategy, Extremum Seeking Control (ESC) has been investigated for VRF systems. Dong et al. (2015) applied the standard centralized ESC scheme to a VRF system that consists of one outdoor unit (ODU) and four IDU’s. Simulation results have indicated the effectiveness of such strategy. As the number of IDU’s increases, the complexity of centralized controllers will increase accordingly. Therefore distributed ESC becomes a natural consideration for VRF systems with large number of IDU’s. In this paper, the Shashahani gradient based distributed ESC scheme proposed by Poveda and Quijano (2013, 2015), is applied to the four-zone VRF system simulated by Dong et al. (2015). In particular, this scheme is enhanced by appending a band-pass filter array at the output to achieve a better “isolation†among individual input channels. A single-input ESC is applied to the ODU, while the distributed ESC is applied to the four IDU’s with each acting as an agent. For each agent, the respective power consumption is used as feedback. The objective is to minimize the total power consumption of all agents. For the ODU ESC, the compressor suction pressure (PCS) set-point is employed as the manipulative input. For the IDU DESC, the evaporator superheat (SH) set-point is used as the manipulative input for each IDU agent. The distributed ESC scheme assumes full information communication among all IDU’s. Simulation study is performed to evaluate the proposed strategy with the Modelica based dynamic simulation model developed by Dong et al. (2015). The ESC is designed under the ambient condition of 35oC and 40 %RH, respectively. The initial temperature of all four IDUs zone is 29oC, and the zone temperature set-point is 26oC. The heat loads for IDU1 through IDU4 are 3000W, 2600W, 2400W and 2000W, respectively. It takes the average total power about 10000 seconds to converge to about 3200W in steady state, with PCS around 13bar, and the SH values of IDU1 through IDU4 at 4.5oC, 4.5oC, 6oC, and 5.5oC, respectively. The total power consumption was decreased from 4500 W to 3200 W, i.e. by 29%. In comparison with the centralized ESC Dong et al. (2015), the steady state error of total power is less than 50w. Work is under way to improve transient and steady-state performance, as well as simulation of other operation modes.  Â

Large Scale Distribution of Massive Dose Vitamin a in Indonesia (a Study of the Operational Aspects)

Suatu pilot proyek pemberian vitamin A dosis tinggi (200.000 IU vitamin A dan 40 IU vitamin E dalam kapsul) sekali tiap 6 bulan kepada anak-anak umur 1-4 tahun di 20 kecamatan Jawa Barat, Tengah dan Timur diadakan mulai 1973. Berdasar perhitungan proyeksi penduduk hasil sensus 1971, di wilayah proyek ini terdapat sejumlah 92.247-101.468 anak sasaran. Pemberian kapsul vitamin A di tiap kecamatan dilakukan oleh dua petugas Puskesmas yang bekerja 3 hari seminggu sedemikian hingga dalam 6 bulan dicapai seluruh anak sasaran dalam wilayah tugasnya. Mereka masing-masing dibantu oleh dua tenaga desa selama bekerja di desa yang bersangkutan. Pemberian kapsul dijalankan secara mengumpulkan anak-anak di suatu tempat di Rukun Tetangga, atau mengunjungi rumah-ke-rumah, atau kombinasi dari keduanya. Tiap anak berumur 1-4 tahun didaftar nama, jenis, umur, nama orang tuanya. Mereka yang berhasil diberi kapsul dicatat. Juga dicatat mereka yang tidak berhasil diberi kapsul, serta alasannya. Pada putaran berikutnya; semua anak yang menjadi berumur 1 tahun diberi kapsul, sedang yang lewat 4 tahun tidak diberi lagi. Hasil penilaian tahun pertama menunjukkan bahwa 76-86 persen dari anak sasaran berhasil diberi kapsul. Jumlah ini menurun dari putaran pertama ke putaran kedua. Sebabnya a.l. musim hujan, sukar mengenali kembali anak yang telah diberi kapsul, dan penolakan orang tua terhadap pemberian kapsul kepada anaknya. Penolakan karena anak muntah dan berak setelah diberi kapsul sebesar setengah persen dari jumlah anak yang diberi kapsul. Tidak diketahui dengan pasti apakah itu gejala hipervitaminosis A. Jumlah anak yang tidak berhasil diberi kapsul rata-rata 20 persen dari anak sasaran. Tidak diketahui apakah kepekaan terhadap defisiensi vitamin A mereka ini sama dengan yang berhasil diberi kapsul. Jika anak yang tidak berhasil diberi kapsul itu justru golongan terpeka, maka cara pencegahan defisiensi vitamin A ini belum berhasil. Perhitungan sementara menunjukkan bahwa biaya pemberian vitamin A dosis tinggi ini per tahun per anak = 54 sen US$, dan akan berkurang bila modal awal dirata-ratakan untuk tahun-tahun berikutnya

A statistical network analysis of the HIV/AIDS epidemics in Cuba

The Cuban contact-tracing detection system set up in 1986 allowed the reconstruction and analysis of the sexual network underlying the epidemic (5,389 vertices and 4,073 edges, giant component of 2,386 nodes and 3,168 edges), shedding light onto the spread of HIV and the role of contact-tracing. Clustering based on modularity optimization provides a better visualization and understanding of the network, in combination with the study of covariates. The graph has a globally low but heterogeneous density, with clusters of high intraconnectivity but low interconnectivity. Though descriptive, our results pave the way for incorporating structure when studying stochastic SIR epidemics spreading on social networks

Rotation Measure Synthesis of Galactic Polarized Emission with the DRAO 26-m Telescope

Radio polarimetry at decimetre wavelengths is the principal source of information on the Galactic magnetic field. The diffuse polarized emission is strongly influenced by Faraday rotation in the magneto-ionic medium and rotation measure is the prime quantity of interest, implying that all Stokes parameters must be measured over wide frequency bands with many frequency channels. The DRAO 26-m Telescope has been equipped with a wideband feed, a polarization transducer to deliver both hands of circular polarization, and a receiver, all operating from 1277 to 1762 MHz. Half-power beamwidth is between 40 and 30 arcminutes. A digital FPGA spectrometer, based on commercially available components, produces all Stokes parameters in 2048 frequency channels over a 485-MHz bandwidth. Signals are digitized to 8 bits and a Fast Fourier Transform is applied to each data stream. Stokes parameters are then generated in each frequency channel. This instrument is in use at DRAO for a Northern sky polarization survey. Observations consist of scans up and down the Meridian at a drive rate of 0.9 degree per minute to give complete coverage of the sky between declinations -30 degree and 90 degree. This paper presents a complete description of the receiver and data acquisition system. Only a small fraction of the frequency band of operation is allocated for radio astronomy, and about 20 percent of the data are lost to interference. The first 8 percent of data from the survey are used for a proof-of-concept study, which has led to the first application of Rotation Measure Synthesis to the diffuse Galactic emission obtained with a single-antenna telescope. We find rotation measure values for the diffuse emission as high as approximately 100 rad per square metre, much higher than recorded in earlier work.Comment: Accepted for publication in The Astronomical Journa

Speech Communication

Contains reports on two research projects.National Science FoundationUnited States Air Force, Cambridge Research Center, Air Research and Development Command (Contract AF19(604)-6102)United States Navy, Office of Naval Research (Contract Nonr-1841(42)

Judging the impact of leadership-development activities on school practice

The nature and effectiveness of professional-development activities should be judged in a way that takes account of both the achievement of intended outcomes and the unintended consequences that may result. Our research project set out to create a robust approach that school staff members could use to assess the impact of professional-development programs on leadership and management practice without being constrained in this judgment by the stated aims of the program. In the process, we identified a number of factors and requirements relevant to a wider audience than that concerned with the development of leadership and management in England. Such an assessment has to rest upon a clear understanding of educational leadership,a clearly articulated model of practice, and a clear model of potential forms of impact. Such foundations, suitably adapted to the subject being addressed, are appropriate for assessing all teacher professional development

Case report: Severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration

INTRODUCTION: Inorganic mercury poisoning is uncommon, but when it occurs it can result in severe, life-threatening features and acute renal failure. Previous reports on the use of extracorporeal procedures such as haemodialysis and haemoperfusion have shown no significant removal of mercury. We report here the successful use of the chelating agent 2,3-dimercaptopropane-1-sulphonate (DMPS), together with continuous veno-venous haemodiafiltration (CVVHDF), in a patient with severe inorganic mercury poisoning. CASE REPORT: A 40-year-old man presented with haematemesis after ingestion of 1 g mercuric sulphate and rapidly deteriorated in the emergency department, requiring intubation and ventilation. His initial blood mercury was 15 580 μg/l. At 4.5 hours after ingestion he was started on DMPS. He rapidly developed acute renal failure and so he was started on CVVHDF for renal support and in an attempt to improve mercury clearance; CVVHDF was continued for 14 days. METHODS: Regular ultradialysate and pre- and post-filtrate blood samples were taken and in addition all ultradialysate generated was collected to determine its mercury content. RESULTS: The total amount of mercury in the ultrafiltrate was 127 mg (12.7% of the ingested dose). The sieving coefficient ranged from 0.13 at 30-hours to 0.02 at 210-hours after ingestion. He developed no neurological features and was discharged from hospital on day 50. Five months after discharge from hospital he remained asymptomatic, with normal creatinine clearance. DISCUSSION: We describe a patient with severe inorganic mercury poisoning in whom full recovery occurred with the early use of the chelating agent DMPS and CVVHDF. There was removal of a significant amount of mercury by CVVHDF. CONCLUSION: We feel that CVVHDF should be considered in patients with inorganic mercury poisoning, particularly those who develop acute renal failure, together with meticulous supportive care and adequate doses of chelation therapy with DMPS