Alphataxin, an Orally Available Small Molecule, Decreases LDL Levels in Mice as a Surrogate for the LDL-Lowering Activity of Alpha-1 Antitrypsin in Humans

The abundant blood protein α1-proteinase inhibitor (α1PI, Αlpha-1, α1-antitrypsin, SerpinA1) is known to bind to the active site of granule-associated human leukocyte elastase (HLE-G). Less well known is that binding of α1PI to cell surface HLE (HLE-CS) induces lymphocyte locomotion mediated by members of the low density lipoprotein receptor family (LDL-RFMs) thereby facilitating low density lipoprotein (LDL) clearance. LDL and α1PI were previously shown to be in negative feedback regulation during transport and clearance of lipoproteins. Further examination herein of the influence of α1PI in lipoprotein regulation using data from a small randomized, double-blind clinical trial shows that treatment of HIV-1-infected individuals with α1PI plasma products lowered apolipoprotein and lipoprotein levels including LDL. Although promising, plasma-purified α1PI is limited in quantity and not a feasible treatment for the vast number of people who need treatment for lowering LDL levels. We sought to develop orally available small molecules to act as surrogates for α1PI. Small molecule β-lactams are highly characterized for their binding to the active site of HLE-G including crystallographic studies at 1.84 Å. Using high throughput screening (HLE-G inhibition, HLE-CS-induced cellular locomotion), we show here that a panel of β-lactams, including the LDL-lowering drug ezetimibe, have the capacity to act as surrogates for α1PI by binding to HLE-G and HLE-CS. Because β-lactams are antibiotics that also have the capacity to promote evolution of antibiotic resistant bacteria, we modified the β-lactam Alphataxin to prevent antibiotic activity. We demonstrate using the diet-induced obesity (DIO) mouse model that Alphataxin, a penam, is as effective in lowering LDL levels as FDA-approved ezetimibe, a monobactam. Non-antibiotic β-lactams provide a promising new therapeutic class of small molecules for lowering LDL levels

Factors affecting the job performance of provincial government Western Cape employees

Public sector management has, through the years, been characterised by a hierarchical system whereby red tape and bureaucracy were the order of the day. Towards the latter part of the apartheid era, management had complete autonomy in the functioning of the human resource management, financial management, operations and so on, of government organisations. Top management, and to a large extent middle management, in most governmental departments comprised predominantly people classified as White. With the launch of the New Democratic Government in 1994, new legislation in the form of the Labour Relations Act of 1995, the Basic Conditions of Employment Act of 1997 and the Employment Equity Act 55 of 1998, was instituted. This transformation heralded an about-turn and rethink by government about policies and strategies governing employees and the workplace; for example, the Labour Relations Act of 1995 restricts the concept of unfair labour practices by employers. The employee’s interest was considered in the new legislation, and is currently part of employee wellbeing programmes initiated by government and incorporated into work schedules. In addition, government has launched strategies such as “Batho Pele” (put people first) and “a home for all” (a Western Cape Provincial Government initiative to improve the image of government) to improve service delivery to communities. The above-mentioned political and legislative changes increasingly required a shift from an autocratic to a team-orientated leadership style and from an exclusively task-orientated to a people-orientated organisational culture. The study explored whether management styles, organisational culture, job satisfaction and job performance have changed in the Provincial Government Western Cape (PGWC) after the advent of democracy in South Africa in 1994. The specific research questions that were pursued included (i) has there been a shift from autocratic to a team-orientated management style in the PGWC?, (ii) has there been a shift from a task-orientated to a people-orientated v organisational culture in the PGWC?, (iii) what were the levels of job satisfaction among the employees, and (iv) how did these changes (if any) in organisational culture, management styles and job satisfaction impact the perceived job performance of these employees. The sample consisted of 100 managers selected from various departments in the PGWC. The empirical results indicated that there has been a shift to a team-orientated management style; that there has not been a shift from a task-orientated to a people-orientated organisational culture; that the perceived levels of job satisfaction and job performance levels are high; and that job satisfaction, especially as it relates to a challenging job content and job fit (in terms of personality, ability and skills), was the main determinant of the perceived job performance of the managers in the PGWC. The managerial implications of these empirical results are discussed and recommendations are proposed on the grounds of these discussions

IPTEKS penyuluhan tentang obesitas dan pengukuran indeks massa tubuh pada masyarakat Kelurahan Malendeng Kecamatan Paal 2 Kota Manado

Obesitas adalah suatu keadaan dimana adanya penimbunan lemak berlebih dari yang diperlukan fungsi tubuh normal. Obesitas merupakan suatu masalah medik yang prevalensinya semakin meningkat setiap tahun. Perbandingan yang normal antara lemak tubuh dan berat badan adalah sekitar 25-30 % pada wanita dan 18-23 % pada pria. Wanita dengan lemak tubuh lebih dari 30 % dan pria dengan lemak tubuh lebih dari 25 % dianggap mengalami obesitas. Masalah kegemukan dan obesitas di Indonesia terjadi pada semua kelompok umur dan pada semua strata ekonomi.Obesitas disebabkan oleh beberapa faktor, diantaranya pola makan berlebih, kurang berolahraga dan faktor lingkungan. Derajat obesitas ditentukan dengan pengukuran indeks massa tubuh. Kelurahan Malendeng kecamatan Paal 2 yang terletak di daerah perkotaan menarik untuk diamati karena obesitas biasanya terjadi di daerah perkotaan. Masalah mitra adalah kurangnya pengetahuan tentang obesitas dan bahayanya bagi kesehatan. Solusi yang ditawarkan adalah transfer ilmu pengetahuan mengenai obesitas dengan menggunakan metode penyuluhan dan kegiatan pengukuran indeks massa tubuh masyarakat kelurahan Malendeng

Magnetron priming by multiple cathodes

A relativistic magnetron priming technique using multiple cathodes is simulated with a three-dimensional, fully electromagnetic, particle-in-cell code. This technique is based on electron emission from N/2N∕2 individual cathodes in an NN-cavity magnetron to prime the ππ mode. In the case of the six-cavity relativistic magnetron, ππ-mode start-oscillation times are reduced up to a factor of 4, and mode competition is suppressed. Most significantly, the highest microwave field power is observed by utilizing three cathodes compared to other recently explored priming techniques.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87840/2/081501_1.pd

Experiments in the control of unbalance response using magnetic bearings

Abstract --Unbalance response is a common vibration problem associated with rotating machinery. For several years, researchers have demonstrated that this vibration could be greatly alleviated for machines using active magnetic bearings through active control. Many of the control strategies employed fall into a class which the authors have termed adaptive open loop control. In this paper, three algorithms in this class are presented and their performances are examined experimentally. These algorithms are (1) a non-recursive control law with simultaneous estimation, (2) a recursive control law with simultaneous estimation, and (3) a recursive control law with gain scheduling according to operating speed. Each algorithms was coded in C and executed on a high-speed, multi-tasking digital controller. The advantages and disadvantages of each algorithm are illustrated by examining experimental results from a laboratory magnetic bearing rotor rig. These results clearly demonstrate the high degree of synchronous vibration attenuation (over 30 dB) which can be achieved with adaptive open loop methods. The response of these algorithms to a sudden change in 'simulated imbalance' is used to evaluate their relative transient performances. These results indicate the benefits of recursive control laws in adapting the synchronous open loop control currents to cancel the vibration. The ability of each of the algorithms to adapt the open loop control during changes in rotor speed is also examined. On this test, the recursive gain scheduled algorithm shows superior performance: rotor midspan vibration is almost completely eliminated over the operating speed range. However, surprisingly, the non-recursive control law shows better performance than the recursive law with simultaneous estimation. This result is explained in terms of the stability of the adaptation process

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control

Report of Seminar on Estate Planning

Reports from the UK/CLE Seminar on Estate Planning held July 19-20, 1974