Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone

Concurrent behavioral and electrophysiological longitudinal recordings for in vivo assessment of aging

Electrophysiological and behavioral alterations, including sleep and cognitive impairments, are critical components of age-related decline and neurodegenerative diseases. In preclinical investigation, many refined techniques are employed to probe these phenotypes, but they are often conducted separately. Herein, we provide a protocol for one-time surgical implantation of EMG wires in the nuchal muscle and a skull-surface EEG headcap in mice, capable of 9-to-12-month recording longevity. All data acquisitions are wireless, making them compatible with simultaneous EEG recording coupled to multiple behavioral tasks, as we demonstrate with locomotion/sleep staging during home-cage video assessments, cognitive testing in the Barnes maze, and sleep disruption. Time-course EEG and EMG data can be accurately mapped to the behavioral phenotype and synchronized with neuronal frequencies for movement and the location to target in the Barnes maze. We discuss critical steps for optimizing headcap surgery and alternative approaches, including increasing the number of EEG channels or utilizing depth electrodes with the system. Combining electrophysiological and behavioral measurements in preclinical models of aging and neurodegeneration has great potential for improving mechanistic and therapeutic assessments and determining early markers of brain disorders

Stamp transferred suspended graphene mechanical resonators for radio-frequency electrical readout

We present a simple micromanipulation technique to transfer suspended graphene flakes onto any substrate and to assemble them with small localized gates into mechanical resonators. The mechanical motion of the graphene is detected using an electrical, radio-frequency (RF) reflection readout scheme where the time-varying graphene capacitor reflects a RF carrier at f=5-6 GHz producing modulation sidebands at f +/- fm. A mechanical resonance frequency up to fm=178 MHz is demonstrated. We find both hardening/softening Duffing effects on different samples, and obtain a critical amplitude of ~40 pm for the onset of nonlinearity in graphene mechanical resonators. Measurements of the quality factor of the mechanical resonance as a function of DC bias voltage Vdc indicate that dissipation due to motion-induced displacement currents in graphene electrode is important at high frequencies and large Vdc

Physical Insights of Low Thermal Expansion Coefficient Electrode Stress Effect on Hafnia-Based Switching Speed

In this report, we investigate the effect of low coefficient of thermal expansion (CTE) metals on the operating speed of hafnium-based oxide capacitance. We found that the cooling process of low CTE metals during rapid thermal annealing (RTA) generates in-plane tensile stresses in the film, This facilitates an increase in the volume fraction of the o-phase and significantly improves the domain switching speed. However, no significant benefit was observed at electric fields less than 1 MV/cm. This is because at low voltage operation, the defective resistance (dead layer) within the interface prevents electron migration and the increased RC delay. Minimizing interface defects will be an important key to extending endurance and retention

Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD

Results from the fly’s eye experiment

We report recently analyzed results on the energy spectrum, and composition of cosmic rays above 0.3 EeV. We observe a break in the spectrum at 3 EeV and a changing composition. The results can be explained by a simple two component model: galactic cosmic rays dominated by heavy primaries and an extragalactic component dominated by light primaries. The observed isotropic arrival direction distribution is consistent with the predictions of this model. A 320 EeV event was also recorded. © 1995 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87516/2/839_1.pd

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs

Evidence for Changing of Cosmic Ray Composition between 10\u3csup\u3e17\u3c/sup\u3e and 10\u3csup\u3e18\u3c/sup\u3e eV from Multicomponent Measurements

The average mass composition of cosmic rays with primary energies between 1017 and 1018eV has been studied using a hybrid detector consisting of the High Resolution Fly\u27s Eye (HiRes) prototype and the MIA muon array. Measurements have been made of the change in the depth of shower maximum and the muon density as a function of energy. The results show that the composition is changing from a heavy to lighter mix as the energy increases. © 2000 The American Physical Society