Miracle-dz/UniFAR-FTUs huggingface dataset:
G Protein–Coupled Receptors, Cholinergic Dysfunction, and Aβ Toxicity in Alzheimer’s Disease

β-amyloid may induce neurodegeneration by affecting G protein–coupled receptor signaling. Alzheimer’s disease (AD) is the most common neurodegenerative disorder afflicting the elderly. Neuropathologically, the AD brain is characterized by amyloid plaques, which are mainly composed of the β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs), which are comprised of hyperphosphorylated aggregates of the tau protein. Few treatments are available, but acetylcholinesterase inhibitors, which increase acetylcholine concentrations in the brain, provide some beneficial effects. Abnormal accumulation of Aβ in the brain is believed to drive disease progression. Although the mechanism of Aβ-mediated toxicity is not clearly understood, new studies provide insight into the effect that Aβ accumulation has on the clustering of a heterotrimeric GTP-binding protein (G protein)–coupled receptor (GPCR), the angiotensin type 2 (AT2) receptor, and the resulting effect on the Gαq/11 family of G proteins, which facilitate GPCR downstream signaling cascades. Assemblies of the AT2 receptor sequester Gαq/11, preventing it from initiating signaling cascades mediated by other GPCRs. The resulting reduction in Gαq/11 binding and signaling by the M1 muscarinic acetylcholine receptor (mAChR) has now been shown to accompany neurodegeneration in an AD mouse model. Thus, these studies provide a potential link between Aβ toxicity, AT2 receptor clustering, and disruption of the M1 mAChR and Gαq/11 signaling pathways, and they contribute to our understanding of the pathogenesis of AD. This Review with 1 figure and 100 citations highlights GPCR-mediated mechanisms of Aβ-induced toxicity in AD. The β-amyloid (Aβ) peptide is associated with the pathogenesis of Alzheimer’s disease (AD). Evidence gathered over the last two decades suggests that the gradual accumulation of soluble and insoluble Aβ peptide species triggers a cascade of events that leads to the clinical manifestation of AD. Aβ accumulation has also been associated with the cholinergic dysfunction observed in AD, which is characterized by diminished acetylcholine release and impaired coupling of the muscarinic acetylcholine receptors (mAChRs) to heterotrimeric GTP-binding proteins (G proteins). Although the mechanism of Aβ-mediated toxicity is not clearly understood, evidence shows that Aβ accumulation has an effect on the oligomerization of the angiotensin II (AngII) AT2 (angiotensin type 2) receptor and sequestration of the Gαq/11 family of G proteins. Sequestration of Gαq/11 results in dysfunctional coupling and signaling between M1 mAChR and Gαq/11 and accompanies neurodegeneration, tau phosphorylation, and neuronal loss in an AD transgenic mouse model. Collectively, these results provide a putative link among Aβ toxicity, AT2 receptor oligomerization, and disruption of the signaling pathway through M1 mAChR and Gαq/11 and potentially contribute to our understanding of the cholinergic deficit observed in AD.
Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation

Responses to ATP play an important role in regulating the signaling and function of a diverse array of cells and tissues. Virtually every type of eukaryotic cell is regulated by adenosine triphosphate (ATP) and other nucleotides, such as uridine triphosphate (UTP), that the cells release themselves (autocrine signaling) or that are released by neighboring cells (paracrine signaling). Signaling in response to released nucleotides occurs through the activation of plasma membrane–localized P2 receptors: the P2X ion channels and the P2Y heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors. Release of ATP and alteration of cellular function also occur under “basal” conditions. Such basal release of ATP, which can be increased by minimal perturbation of cells through physical or chemical stimuli, influences a wide array of physiological events, including tissue blood flow, ion transport, growth and metastatic potential of malignant cells, endocrine and neuronal activity, neural development, musculoskeletal and renal function, stem cell proliferation, and response to pathogens. This Review, which contains two figures and 216 references, discusses the diverse array of receptors for ATP (and its major hydrolytic product adenosine) and the range of enzymes (including ecto–adenosine triphosphatases and kinases) that regulate extracellular concentrations of ATP, which create a highly versatile and tightly regulated system for the regulation of cell and tissue function by extracellular ATP that is derived from intracellular pools of nucleotides. Cells release adenosine triphosphate (ATP), which activates plasma membrane–localized P2X and P2Y receptors and thereby modulates cellular function in an autocrine or paracrine manner. Release of ATP and the subsequent activation of P2 receptors help establish the basal level of activation (sometimes termed "the set point") for signal transduction pathways and regulate a wide array of responses that include tissue blood flow, ion transport, cell volume regulation, neuronal signaling, and host-pathogen interactions. Basal release and autocrine or paracrine responses to ATP are multifunctional, evolutionarily conserved, and provide an economical means for the modulation of cell, tissue, and organismal biology.
New Regulator for Energy Signaling Pathway in Plants Highlights Conservation Among Species

The kinase CIPK links plant pathways involved in oxygen-sensing and carbohydrate metabolism. The “low-energy checkpoint” SNF1-related protein kinases, which are conserved in all eukaryotes, play an important role in cellular metabolic adaptation to differences in energy and oxygen availability. Although the signaling pathways involved in such metabolic adaptations are well understood in yeast and mammals, they have been poorly understood in plants. A recent study revealed that calcineurin B–like interacting protein kinase 15 (CIPK15) acted as a global regulator of such adaptations, linking the response to O2 deficiency with the response to carbohydrate starvation in rice (Oryza sativa). Knockout mutants of Nipponbare rice CIPK15 failed to initiate transcription of the glycolytic enzymes α-amylase 3 and alcohol dehydrogenase 2, which mediate fermentative metabolism for adenosine triphosphate generation under anaerobic conditions. Targeted manipulation of OsCIPK15 might facilitate rice cultivation and ensure agricultural productivity in regions subject to flooding. Here, we highlight the importance of the energy- and oxygen-sensing pathway indicated by its conservation among different eukaryotic kingdoms.
The Quality of Community Reintegration Planning for Child Molesters

Research on the causal factors underlying sex offender recidivism has not considered the success or failure of the reintegration process by which the offender rejoins the community after prison. The authors developed a coding protocol to measure the quality and comprehensiveness of reintegration planning for sex offenders. The protocol was retrospectively applied to groups of recidivists and nonrecidivists who were matched on static risk level and follow-up time. The protocol demonstrated adequate reliability. Compared to nonrecidivists, recidivists had significantly lower scores relating to accommodation, employment, and the Good Lives Model secondary goods, as well as lower total reintegration plan scores. ANCOVAs showed that when IQ and level of sexual deviance were controlled for, accommodation (a place to live) was significantly related to sexual recidivism and the Good Lives Model—secondary goods was significantly related to any recidivism. These results suggest that poor reintegration planning may be a risk factor for recidivism.
Domain Recombination: A Workhorse for Evolutionary Innovation

Firm evidence for domain shuffling as a means of evolving new functions might lead us to the creation of combinations of practical benefit. Although the combination of modular domains within proteins has been proposed as a determining feature of evolutionary innovation and flexibility, direct evidence for this mechanism of evolution has been sketchy. Two papers, one creating new domain combinations in the yeast mating pathway and another involving a comprehensive analysis of protein function and domain architecture across major organisms, have provided firm evidence that the recombining of domains can lead to evolutionary innovation. The results will guide future studies in synthetic and evolutionary biology.
Apoptosis, Stem Cells, and Tissue Regeneration

Cells undergoing stress- or injury-induced apoptosis can stimulate tissue regeneration by promoting stem or progenitor cell proliferation. Tissue regeneration after wounding or amputation generally requires cell proliferation. Work in several model organisms, including Drosophila, Hydra, Xenopus, and mouse, revealed a surprising function for caspases in cell proliferation after tissue damage, in addition to their known role in a form of cell death called apoptosis. In apoptotic cells, caspases can stimulate the production of secreted cytokines, such as Wnt, bone morphogenetic protein (BMP), transforming growth factor–β (TGF-β), Hedgehog family members, and prostaglandins, which in turn induce proliferation of neighboring cells, thus promoting tissue regeneration and homeostasis. These pathways can also contribute to tumorigenesis. This Review summarizes findings on this phenomenon, termed “apoptosis-induced compensatory proliferation,” and contains three figures and 110 references. Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in response to external injury, wounding, or amputation (epimorphic regeneration). Model organisms that display remarkable regenerative capacity include amphibians, planarians, Hydra, and the vertebrate liver. In addition, several mammalian organs, including the skin, gut, kidney, muscle, and even the human nervous system, have some ability to replace spent or damaged cells. Although the regenerative response is complex, it typically involves the induction of new cell proliferation through formation of a blastema, followed by cell specification, differentiation, and patterning. Stem cells and undifferentiated progenitor cells play an important role in both tissue homeostasis and tissue regeneration. Stem cells are typically quiescent or passing slowly through the cell cycle in adult tissues, but they can be activated in response to cell loss and wounding. A series of studies, mostly performed in Drosophila as well as in Hydra, Xenopus, and mouse, has revealed an unexpected role of apoptotic caspases in the production of mitogenic signals that stimulate the proliferation of stem and progenitor cells to aid in tissue regeneration. This Review summarizes some of the key findings and discusses links to stem cell biology and cancer.
Citrullination in MS: Potential for a new diagnostic test

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease, which predominantly affects the white matter of the central nervous system (CNS). It is the most common neurological disease in young adults with a mean age of onset of 30 years (Trapp and Nave, 2008). The disease is characterized by destruction of the myelin sheath, which insulates the axons of nerves, resulting in lesions of demyelinated axon fibres (Lassman, 2004). Within these lesions there is infi ltration of T and B lymphocytes and macrophages, as well as locally activated CNS resident cells, astrocytes and microglia (Musse and Harauz, 2007).
Transference of Strength and Power Adaptation to Sports Performance—Horizontal and Vertical Force Production

THE TRAINING OF HORIZONTAL PROPULSIVE FORCE GENERATION IS ONE ASPECT OF MANY SPORTS THAT IS NOT EASILY SIMULATED WITH TRADITIONAL GYM-BASED RESISTANCE TRAINING METHODS, WHICH PRINCIPALLY WORK THE LEG MUSCULATURE IN A VERTICAL DIRECTION. GIVEN THAT MOST MOTION INVOLVES AN INTEGRATION OF BOTH VERTICAL AND HORIZONTAL FORCE PRODUCTION, TRANSFERENCE OF GYM-BASED STRENGTH GAINS MAY BE IMPROVED IF EXERCISES WERE USED THAT INVOLVED BOTH VERTICAL AND HORIZONTAL FORCE PRODUCTION.
Endometrial Intraepithelial Carcinoma (EIC)/Serous (Type 2) Surface Cancer

Serous (type 2) endometrial carcinomas are uniformly high grade, estrogen independent, often found in thin, atrophic endometria. This contrasts to the thickened endometrial stripe seen with endometrioid (type 1) carcinomas. In further distinction from type 1 carcinomas, type 2 carcinomas are known to metastasize widely without apparent myometrial invasion and without an identifiable stromal response—hence the difficulty in classifying a lesion as truly “intraepithelial” without data concerning its absence from usual sites of tumor metastasis. Endometrial intraepithelial carcinoma can be diagnosed cytologically by the findings of: marked nuclear atypia with enlarged nucleoli; confluent, strong p53 nuclear reactivity; and a marked increase in Ki-67 reactive nuclei. The very high Ki-67 proliferation index of these lesions exposes neoplastic epithelium that contrasts with surrounding atrophic epithelium. The p53 labeling is uniformly intense and confluent among malignant nuclei, unlike characteristically weak, spotty, or absent p53 labeling of early type 1 carcinoma and atypical hyperplasia.
Dephosphorylation of the adaptor LAT and phospholipase C–γ by SHP-1 inhibits natural killer cell cytotoxicity

Researchers identify targets of a phosphatase that inhibits the activity of natural killer cells. Keeping NK cells in check Natural killer (NK) cells are immune cells that recognize and kill virally infected cells and tumor cells. Whether an NK cell becomes activated or inhibited depends on the relative extent of signaling by cell surface activating or inhibitory receptors that are engaged. Inhibitory receptor signaling activates the inhibitory phosphatase SHP-1. In experiments with human NK cells, Matalon et al. identified the adaptor protein LAT and two members of the phospholipase C–γ family as substrates of SHP-1. Inhibitory receptor signaling not only resulted in dephosphorylation of LAT, which reduced intracellular Ca2+ signaling by activating receptors, but also promoted LAT ubiquitylation and degradation, further dampening NK cell function. Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain–containing protein tyrosine phosphatase–1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C–γ1 (PLC-γ1) and PLC-γ2 are SHP-1 substrates. Dephosphorylation of Tyr132 in LAT by SHP-1 in NK cells abrogated the recruitment of PLC-γ1 and PLC-γ2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells.
Nativization of English Language in a Multilingual Setting: The Example of Nigeria

This paper discusses the history of the English language in Nigeria, its international status and its numerous functions. The author maintains that the English language has adapted itself to the different exigencies, particularly the linguistic and cultural contexts of its use. The author gives features and nuances of the English that are peculiar to the Nigerian users to show the nativization of the English language in Nigeria. She opines that the English language has continued to exist in a multilingual setting like Nigeria where an indigenous national language has not evolved. The author discusses some scholarly criteria for the standardization of the world Englishes, which she maintains, must be respected. She also reinforces that Nigerian English is a variety of the world Englishes. She concludes that any discussion of nativization or domestication must not, in any way, jettison social acceptability and intelligibility so that Nigerian English will enjoy a wide and social use. DOI: 10.5901/ajis.2014. v3n6p485
Review : Production and functionality of active peptides from milk

In recent years, research on the production of active peptides obtained from milk and their potential functionality has grown, to a great extent. Bioactive peptides have been defined as specific protein fragments that have a positive impact on body functions or conditions, and they may ultimately have an influence on health. Individual proteins of casein or milk-derived products such as cheese and yogurt have been used as a protein source to study the isolation and activity of peptides with several applications. Currently, the milk whey waste obtained in the production of cheese also represents a protein source from which active peptides could be isolated with potential industrial applications. The active properties of milk peptides and the results found with regard to their physiological effects have led to the classification of peptides as belonging to the group of ingredients of protein nature, appropriate for use in functional foods or pharmaceutical formulations. In this study, the main peptides obtained from milk protein and the past research studies about its production and biological activities will be explained. Second, an analysis will be made on the methods to determinate the biological activities, the separation of bioactive peptides and its structure identification. All of these form the base required to obtain synthetic peptides. Finally, we explain the experimental animal and human trials done in the past years. Nevertheless, more research is required on the design and implementation of equipment for the industrial production and separation of peptides. In addition, different authors suggest that more emphasis should therefore be given to preclinical studies, proving that results are consistent and that effects are demonstrated repeatedly by several research human groups.
Demanding work schedules and mental health in nursing assistants working in nursing homes

Nursing home assistants have physically and emotionally challenging jobs, and they often work demanding schedules in order to provide 24-h care. While the physical effects of demanding work schedules have been studied, little is known about the impact on mental health. This study explored the relationship between demanding scheduling variables and mental health indicators of depression, anxiety and somatization. A cross-section of 473 US female nursing assistants working in nursing homes was surveyed. Work schedule characteristics included shiftwork, hours per day and week, days per week, number of weekends per month, number of double shifts per month, breaks, and number of jobs worked. Working two or more double-shifts per month was associated with increased risk for all mental health indicators, and working 6–7 days per week was associated with depression and somatization. There was a trend for increasing odds of adverse mental health with increased numbers of demanding work schedule factors. The odds of depression was increased four-fold when working 50+ h/week, more than two weekends/month and more than two double shifts/month. Providing work schedules that are less unhealthy may have implications for both worker retention and the quality of care delivered to nursing home residents.
Hyperspectral reflectance characteristics for Spring Wheat in different drought intimidate

Crop is often suffered from drought in semi-arid rainfed agriculture area. Diagnosis of crop drought status is critical for prediction of agriculture drought in this area. Two experiments were conducted for find out spr-wheat canopy spectral characters measurement in different water control status in field in 2007 and 2008, and the experiment included two cultivars and four levels of drought. Hyperspectral canopy and leaf reflectance (350–2500 nm) data recorded at various growth stages and different drought levels were measured by an ASD Field Spec Pro FR2500 in different stages, and the biophysical Parameters were measured at the same time. The hyperspectral reflectance characteristics for Spring Wheat in different drought intimidate at canopy level and the impact of different drought to the biochemical properties of the spring wheat were analyzed. The results revealed following concludes: firstly, the chlorophyll absorb vale change shallow along with the drought level increased, and the reflectance in near infrared region decreased, and the water absorb vale changed shallow at the same time; secondly, the band in 970nm, 1200nm, 1650nm have a highly sensitivity to the drought change, they are the perfect band for the water stress indices design; thirdly, the red edge (Sred)of the spectral is a most sensitivity index for the drought monitoring and the change range From severe drought to no drought is in 718nm–730nm. And when the drought increased the red edge shows ‘blue shift’ phenomena, and the slope of red edge (Dλred) and area of red edge (Sred) of the canopy and leaf spectra are decrease; Fourthly, the leaf water content, leaf area index (LAI) and chlorophyll decreased due to the drought impact, especially, the chlorophyll content, and the spectral change of the spring wheat result in the water content is main by the changing of the chlorophyll.
Project 523: transformation of Artemisinin from traditional Chinese medicine to mainstream anti- malaria chemotherapy

Artemisinin (Qing Hao in Chinese) has been recommended for the treatment of intermittent fever in China since the era of the famous physician Ge Hong. In 1967, the Mao-led Chinese government established a major multidisciplinary research program – Project 523 – for development of effective malaria chemotherapy from local herbs. Following clinical trials which demonstrated its superiority and effectiveness, Qing Hao derivatives currently constitute the mainstay of malaria treatment. The 2010 World malaria report documented malaria-related deaths of 800,000 people yearly, mainly in Africa and Asia. This review highlights the evolution of Qing Hao from its traditional Chinese medicine origins to a cutting edge antimalarial drug produced by Novartis, one of the world’s leading pharmaceutical companies. Implications for future transition of complementary treatments to mainstream therapies are discussed.