Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons.

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aß, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

Thermoactivated cement from construction and demolition waste for pavement base stabilization: A case study in Brazil.

Construction and demolition waste (CDW) worldwide generation accounts 10 billion tonnes yearly. The major fraction is landfilled requiring innovative recycling methods to reduce the associated environmental impacts and to increase its circularity. Our study demonstrated the feasibility of using different CDW fines to develop recycled cements and optimized the content of CDW recycled cements with well-graded crushed stone (WGCS) for use as pavement base layer. We scaled up the study obtaining CDW cement and aggregates from a local recycling plant, as well as pilot pavement sections designed, constructed and field deflections measured. As results, the CDW cement pastes exhibited accumulated heat values of up to 111 J g-1 and achieved a compressive strength of approximately 16 MPa. The unconfined compressive strength and resilient modulus (RM) achieved using CDW cement and WGCS were 2-3 and >3000 MPa, respectively. The sections constructed using CDW cement exhibited intermediate behaviour compared to those obtained using reference materials (6% Portland cement-WGCS and a conventional granular base made using WGCS). The deflection decreased over time owing to the pozzolanic reaction.

A Ku-Band GaN-on-Si MMIC Power Amplifier with an Asymmetrical Output Combiner.

In this paper, a microwave monolithic integrated circuit (MMIC) high-power amplifier (HPA) for Ku-band active radar applications based on gallium nitride on silicon (GaN-on-Si) is presented. The design is based on a three-stage architecture and was implemented using the D01GH technology provided by OMMIC foundry. Details on the architecture definition and design process to maximize delivered power are provided along with stability and thermal analyses. To optimize the amplifier performance, an asymmetry was included at the output combiner. Experimental results show that the HPA achieves a 39.5 dBm pulsed-mode output power, a peak linear gain of 23 dB, a drain efficiency of 27%, and good input/output matching in the 16-19 GHz frequency range. The chip area is 5 × 3.5 mm2 and for the measurements was mounted on a custom-made module. These results demonstrate that GaN-on-Si-based Solid-State Power Amplifiers (SSPAs) can be used for the implementation of Ku-band active radars.

Local glutamate-mediated dendritic plateau potentials change the state of the cortical pyramidal neuron.

Dendritic spikes in thin dendritic branches (basal and oblique dendrites) are traditionally inferred from spikelets measured in the cell body. Here, we used laser-spot voltage-sensitive dye imaging in cortical pyramidal neurons (rat brain slices) to investigate the voltage waveforms of dendritic potentials occurring in response to spatially restricted glutamatergic inputs. Local dendritic potentials lasted 200-500 ms and propagated to the cell body, where they caused sustained 10- to 20-mV depolarizations. Plateau potentials propagating from dendrite to soma and action potentials propagating from soma to dendrite created complex voltage waveforms in the middle of the thin basal dendrite, comprised of local sodium spikelets, local plateau potentials, and backpropagating action potentials, superimposed on each other. Our model replicated these voltage waveforms across a gradient of glutamatergic stimulation intensities. The model then predicted that somatic input resistance (Rin) and membrane time constant (tau) may be reduced during dendritic plateau potential. We then tested these model predictions in real neurons and found that the model correctly predicted the direction of Rin and tau change but not the magnitude. In summary, dendritic plateau potentials occurring in basal and oblique branches put pyramidal neurons into an activated neuronal state ("prepared state"), characterized by depolarized membrane potential and smaller but faster membrane responses. The prepared state provides a time window of 200-500 ms, during which cortical neurons are particularly excitable and capable of following afferent inputs. At the network level, this predicts that sets of cells with simultaneous plateaus would provide cellular substrate for the formation of functional neuronal ensembles.NEW & NOTEWORTHY In cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials with voltage imaging and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state: a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs.

Single-Event Transients in an IEEE 802.15.4 RF Receiver for Wireless Sensor Networks.

This paper presents a procedure to analyse the effects of radiation in an IEEE 802.15.4 RF receiver for wireless sensor networks (WSNs). Specifically, single-event transients (SETs) represent one of the greatest threats to the adequate performance of electronic communication devices in high-radiation environments. The proposed procedure consists in injecting current pulses in sensitive nodes of the receiver and analysing how they propagate through the different circuits that form the receiver. In order to perform this analysis, a Complementary Metal Oxide Semiconductor (CMOS) low-IF receiver has been designed using a 0.18 µm technology from the foundry UMC. In order to analyse the effect of single-event transients in this receiver, it has been studied how current pulses generated in the low-noise amplifier propagate down the receiver chain. The effect of the different circuits that form the receiver on this kind of pulse has been studied prior to the analysis of the complete receiver. First, the effect of SETs in low-noise amplifiers was analysed. Then, the propagation of pulses through mixers was studied. The effect of filters in the analysed current pulses has also been studied. Regarding the analysis of the designed RF receiver, an amplitude and phase shift was observed under the presence of SETs.

Amyloid pathology-produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites.

INTRODUCTION: Alzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. Decreased expression of the calcium-binding protein cal- bindin-D28K (CB) might be a susceptibility factor for AD. The subiculum is affected early in AD, for unknown reasons. METHODS: In AD, CB knock-out and control mice fluorescence Ca2+ imaging combined with patch clamp were used to characterize Ca2+ dynamics, resting Ca2+ , and Ca2+ -buffering capacity in subicular neurons. CB expression levels in wild-type and AD mice were also analyzed. RESULTS: The subiculum and dentate gyrus of wild-type mice showed age-related decline in CB expression not observed in AD mice. Resting Ca2+ and Ca2+ -buffering capacity was increased in aged AD mice subicular dendrites. Modeling suggests that AD calcium changes can be explained by alterations of Ca2+ extrusion pumps rather than by buffers. DISCUSSION: Overall, abnormal Ca2+ homeostasis in AD has an age dependency that comprises multiple mechanisms, including compensatory processes.

Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife and affects specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls. In contrast to a region in the anterior caudate, in which dysfunction was linked to genotype independent of phenotype, a region in the posterior body of the caudate was differentially associated with disease phenotype. Guided by these observations, we harvested regions from the anterior and posterior body of the caudate in postmortem control and HD human brain tissue. Gene-expression profiling identified two molecules whose expression levels were most strongly correlated with regional vulnerability - protein phosphatase 1 regulatory subunit 7 (PPP1R7) and Wnt inhibitory factor-1 (WIF-1). To verify and potentially extend these findings, we turned to the YAC128 (C57BL/6J) HD transgenic mice. By fMRI we longitudinally mapped CBV in transgenic and wildtype (WT) mice, and over time, abnormally low fMRI signal emerged selectively in the dorsal striatum. A relatively unaffected brain region, primary somatosensory cortex (S1), was used as a control. Both dorsal striatum and S1 were harvested from transgenic and WT mice and molecular analysis confirmed that PPP1R7 deficiency was strongly correlated with the phenotype. Together, converging findings in human HD patients and this HD mouse model suggest a functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability.

A 17.8-20.2 GHz Compact Vector-Sum Phase Shifter in 130 nm SiGe BiCMOS Technology for LEO Gateways Receivers.

This paper presents a novel and compact vector modulator (VM) architecture implemented in 130 nm SiGe BiCMOS technology. The design is suitable for use in receive phased arrays for the gateways of major low Earth orbit (LEO) constellations that operate in the 17.8 to 20.2 GHz frequency range. The proposed architecture uses four variable gain amplifiers (VGA) that are active at any given time and are switched to generate the four quadrants. Compared to conventional architectures, this structure is more compact and produces double the output amplitude. The design offers 6-bit phase control for 360°, and the total root mean square (RMS) phase and gain errors are 2.36° and 1.46 dB, respectively. The design occupies an area of 1309.4 µm × 1783.8 µm (including pads).

Factors influencing temporary wood waste generation in high-rise building construction.

In Brazil, the use of wood in construction is primarily temporary, and it can represent a great percentage of construction waste. It is typically discarded with minimal reuse or recycling. As landfill wood disposal could result in methane emissions and/or leaching of hazardous constituents polluting water or soil, the implementation of temporary wood waste reduction strategies must be a critical issue for local construction companies. To manage and control wood waste generation, including setting some reduction goals, it is necessary to identify the influencing factors and ways to quantitatively predict their relative contributions. This study uses a multiple regression statistical model to estimate the amount of temporary wood waste generated in the construction of high-rise buildings by considering the influencing factors related to the design/construction as well as site and safety installations. The case study includes 22 high-rise residential buildings. The regression model predicted approximately 89% of the factors involved in the generation of wood waste in similar constructions. The dependent variables that had an influence on the amount of wood waste are related to design features ('number of floors'), structural construction system ('in situ moulded concrete volume'), and site and safety installations ('site wood fence' and 'wood use rate'). Ways of minimising wood waste generation and the contributions of each type of temporary wood use were discussed.

Genetic underpinnings in Alzheimer's disease - a review.

In this review, we discuss the genetic etiologies of Alzheimer's disease (AD). Furthermore, we review genetic links to protein signaling pathways as novel pharmacological targets to treat AD. Moreover, we also discuss the clumps of AD-m ediated genes according to their single nucleotide polymorphism mutations. Rigorous data mining approaches justified the significant role of genes in AD prevalence. Pedigree analysis and twin studies suggest that genetic components are part of the etiology, rather than only being risk factors for AD. The first autosomal dominant mutation in the amyloid precursor protein (APP) gene was described in 1991. Later, AD was also associated with mutated early-onset (presenilin 1/2, PSEN1/2 and APP) and late-onset (apolipoprotein E, ApoE) genes. Genome-wide association and linkage analysis studies with identified multiple genomic areas have implications for the treatment of AD. We conclude this review with future directions and clinical implications of genetic research in AD.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Separability studies of construction and demolition waste recycled sand.

The quality of recycled aggregates from construction and demolition waste (CDW) is strictly related to the content of porous and low strength phases, and specifically to the patches of cement that remain attached to the surface of natural aggregates. This phase increases water absorption and compromises the consistency and strength of concrete made from recycled aggregates. Mineral processing has been applied to CDW recycling to remove the patches of adhered cement paste on coarse recycled aggregates. The recycled fine fraction is usually disregarded due to its high content of porous phases despite representing around 50% of the total waste. This paper focus on laboratory mineral separability studies for removing particles with a high content of cement paste from natural fine aggregate particles (quartz/feldspars). The procedure achieved processing of CDW by tertiary impact crushing to produce sand, followed by sieving and density and magnetic separability studies. The attained results confirmed that both methods were effective in reducing cement paste content and producing significant mass recovery (80% for density concentration and 60% for magnetic separation). The production of recycled sand contributes to the sustainability of the construction environment by reducing both the consumption of raw materials and disposal of CDW, particularly in large Brazilian centers with a low quantity of sand and increasing costs of this material due to long transportation distances.

Resíduos de construção e demolição: avaliação de métodos de quantificação / Construction and demolition waste: evaluation of quantification methods

Neste trabalho, estimou-se a gerão dos resíduos de construção e demolição por dois métodos de quantificação, um indireto e outro direto, considerando-se a produção advinda dos agentes informais e formais. O método indireto considerou a área construída das edificações (construção) e transformação dos pontos de ligação de água e luz instalados (reforma). O método direto identificou a geração advinda de agentes informais e formais nos pontos de disposição finais em diferentes regiões do município, empregando-se o conceito de balanço de massa. Não é possível quantificar a geração de resíduos de construção e demolição dos agentes informais (reformas) por meio de dados indiretos relacionados Às transformações dos pontos de água no município. Há indícios de que as transformações dos pontos de energia elétrica sejam um indicador indireto mais preciso, podendo evitar a dispendiosa quantificação direta.

In this paper, construction and demolition waste generation was estimated by two quantification methods, one direct and other indirect, regarding informal and formal generators. Construction area and transformation of the points of water and energy were applied for indirect quantification method. For the direct one, volume of dumping areas associated with informal and formal generators in different regions of municipality were quantified and the mass balance was applied. Indirect quantification of informal generators by transformation points of water is not precise. There are evidences that transformation points of energy can be more precise, avoiding costly direct construction and demolition waste quantification method.