Improving macromolecular electrostatics calculations

Electrostatic interactions play a key role in many aspects ofprotein engineering. Consequently, much effort has been putinto the design of software for calculating electrostatic fieldsaround macromolecules. We show that optimization of hydrogenbonding networks can improve both the results of pK_a calculationsand the results of electrostatic calculations performed by commonlyused programs such as DelPhi. Further optimization can oftenbe achieved by flipping the side chains of asparagine, histidineand glutamine around their 2, 2 and 3 torsion angles, respectively,when this improves the local hydrogen bonding network. Theseoptimizations are applied to some well characterized proteins:BPTI, hen egg white lysozyme and superoxide dismutase. A searchfor flipped residues in the PDB revealed that significant improvementsin electrostatic calculations in or near the active site ofenzymes can be expected for about one quarter of all enzymesin the PDB.     

Training overhead for decoding random linear network codes in wireless networks

We consider multicast communications from a single source to multiple destinations through a wireless network with unreliable links. Random linear network coding achieves the min-cut flow capacity; however, additional overhead is needed for end-to-end error protection and to communicate the network coding matrix to each destination. We present a joint coding and training scheme in which training bits are appended to each source packet, and the channel code is applied across both the training and data. This scheme allows each destination to decode jointly the network coding matrix along with the data without knowledge of the network topology. It also balances the reliability of communicating the network coding matrices with the reliability of data detection. The throughput for this scheme, accounting for overhead, is characterized as a function of the packet size, channel properties (error and erasure statistics), number of independent messages, and field size. We also compare the performance with that obtained by individual channel coding of training and data. Numerical results are presented for a grid network that illustrate the reduction in throughput due to overhead.     

Signature optimization for CDMA with limited feedback

We study the performance of joint signature-receiver optimization for direct-sequence code-division multiple access (DS-CDMA) with limited feedback. The receiver for a particular user selects the signature from a signature codebook, and relays the corresponding B index bits to the transmitter over a noiseless channel. We study the performance of a random vector quantization (RVQ) scheme in which the codebook entries are independent and isotropically distributed. Assuming the interfering signatures are independent, and have independent and identically distributed (i.i.d.) elements, we evaluate the received signal-to-interference plus noise ratio (SINR) in the large system limit as the number of users, processing gain, and feedback bits B all tend to infinity with fixed ratios. This SINR is evaluated for both the matched filter and linear minimum mean-squared error (MMSE) receivers. Furthermore, we show that this large system SINR is the maximum that can be achieved over any sequence of codebooks. Numerical results show that with the MMSE receiver, one feedback bit per signature coefficient achieves close to single-user performance. We also consider a less complex and suboptimal reduced-rank signature optimization scheme in which the user's signature is constrained to lie in a lower dimensional subspace. The optimal subspace coefficients are scalar-quantized and relayed to the transmitter. The large system performance of the quantized reduced-rank scheme can be approximated, and numerical results show that it performs in the vicinity of the RVQ bound. Finally, we extend our analysis to the scenario in which a subset of users optimize their signatures in the presence of random interference.     

Motor,Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189

We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50–60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.     

Fatty acid profile and affective dysregulation in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a high co-occurrence with affective dysregulation. Affective disorders have been associated with specific changes in the PUFA and cholesterol profile. In IBS, similar changes may be present as have been reported in patients with affective disorders. This exploratory study investigates (i) the level of affective dysregulation (AD) in IBS patients and healthy controls; (ii) PUFA and cholesterol profiles in IBS patients compared with controls; and (iii) associations between PUFA and cholesterol parameters with the level of AD. Blood samples were obtained for determination of the FA composition of plasma phospholipids and serum cholesterol in 23 diarrheapredominant IBS patients and 23 healthy matched controls. AD was scored using the Symptom Check List depression scale, the Hospital Anxiety and Depression Scale, and the Hamilton Depression Rating Scale. The level of AD was higher in IBS patients compared with controls. PUFA and cholesterol profiles did not differ significantly between groups. Total n−3 PUFA and cholesterol were significantly negatively associated and the ratio of n−6 to n−3 PUFA and the ratio of arachidonic acid to EPA were significantly positively associated with the level of AD. The findings of the present study reveal that AD was higher in IBS patients compared with healthy controls and that changes in PUFA and cholesterol profiles were significantly associated with the level of AD. These results warrant further studies regarding the role of PUFA and cholesterol status in the co-occurrence of AD and functional gastrointestinal disorders.     

Rheology of fluids measured by correlation force spectroscopy

We describe a method, correlation force spectrometry (CFS), which characterizes fluids through measurement of the correlations between the thermally stimulated vibrations of two closely spaced micrometer-scale cantilevers in fluid. We discuss a major application: measurement of the rheological properties of fluids at high frequency and high spatial resolution. Use of CFS as a rheometer is validated by comparison between experimental data and finite element modeling of the deterministic ring-down of cantilevers using the known viscosity of fluids. The data can also be accurately fitted using a harmonic oscillator model, which can be used for rapid rheometric measurements after calibration. The method is non-invasive, uses a very small amount of fluid, and has no actively moving parts. It can also be used to analyze the rheology of complex fluids. We use CFS to show that (non-Newtonian) aqueous polyethylene oxide solution can be modeled approximately by incorporating an elastic spring between the cantilevers.     

Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases

OBJECTIVE: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. METHOD: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examination. RESULTS: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in the two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of homovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA.     

Distributed resource allocation schemes

In this article, we discuss distributed resource allocation schemes in which each transmitter determines its allocation autonomously, based on the exchange of interference prices. These schemes have been primarily motivated by the common model for spectrum sharing in which a user or service provider may transmit in a designated band provided that they abide by certain rules (e.g., a standard such as 802.11). An attractive property of these schemes is that they are scalable, i.e., the information exchange and overhead can be adapted according to the size of the network.     

Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients

Selective serotonin reuptake inhibitors (SSRIs) are the 'new' drugs of first choice for the treatment of depression in the older patient. Systematic studies on the effects of SSRIs on cardiac function are scarce, despite the high prevalence of cardiac disorders in the older depressed patient. This is a study which systematically assessed cardiac function by echocardiography in middle-aged and elderly depressed patients treated with SSRI. In a double-blind randomized trial, 20 patients were assigned to receive fluvoxamine 100 mg/day [DOSAGE ERROR CORRECTED] or fluoxetine 20 mg/day [DOSAGE ERROR CORRECTED] for 6 weeks. Cardiac function was assessed by left ventricle ejection fraction, aortic flow integral and early or passive/late or active mitral inflow, and electrocardiography. Neither SSRI significantly affected cardiac function. Compared with patients without a history of myocardial infarction and/or hypertension, patients with such a history showed a significant improvement in left ventricular ejection fraction. Despite our small study sample, these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely.