Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells*

Background: The role of the amyloid precursor protein (APP) in neural stem/progenitor cell (NSPC) proliferation is poorly understood. Results: Immunodepletion of cystatin C from NSPC conditioned medium abrogated an effect of APP on NSPC proliferation. Conclusion: Cystatin C mediates APP-induced NSPC proliferation. Significance: The results increase understanding of mechanisms promoting NSPC survival and differentiation. The amyloid precursor protein (APP) is well studied for its role in Alzheimer disease. However, little is known about its normal function. In this study, we examined the role of APP in neural stem/progenitor cell (NSPC) proliferation. NSPCs derived from APP-overexpressing Tg2576 transgenic mice proliferated more rapidly than NSPCs from the corresponding background strain (C57Bl/6xSJL) wild-type mice. In contrast, NSPCs from APP knock-out (APP-KO) mice had reduced proliferation rates when compared with NSPCs from the corresponding background strain (C57Bl/6). A secreted factor, identified as cystatin C, was found to be responsible for this effect. Levels of cystatin C were higher in the Tg2576 conditioned medium and lower in the APP-KO conditioned medium. Furthermore, immunodepletion of cystatin C from the conditioned medium completely removed the ability of the conditioned medium to increase NSPC proliferation. The results demonstrate that APP expression stimulates NSPC proliferation and that this effect is mediated via an increase in cystatin C secretion.
Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin*

Background: It remains unclear why vasopressin induces greater antidiuresis through V2R than does oxytocin. Results: Vasopressin sustains cAMP signaling during V2R internalization, a process promoted by β-arrestins, and is halted by the retromer complex. Conclusion: This new noncanonical model of GPCR signaling differentiates the actions of vasopressin and oxytocin. Significance: This emerging model may explain the physiological bias between ligands. The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes. Contrary to the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R complex yet extend rather than shorten the generation of cAMP. Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na+ transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor, these data support the existence of a novel “noncanonical” regulatory pathway for GPCR activation and response termination, via the sequential action of β-arrestin and the retromer complex.
The strategic use of sex in wild female western gorillas

Human females, unlike most mammals, are sexually active outside of fertile periods. This decoupling of sexual behavior from its conceptive function has had an enormous impact on human social relationships, and yet we know little about why there was selection for nonconceptive mating. Here we examine one form of nonconceptive mating, the mating that occurs during pregnancy or post‐conceptive (PC) mating, in wild western gorillas (Gorilla gorilla). Using a near complete mating record for five females during gestation, we show that pregnant females varied in the timing and frequency of mating, and used PC mating conditionally, synchronizing copulations to occur on days when other females mated, and refraining from mating for lengthy periods when no other females mated. As pregnant females mated exclusively with the same male before and after conception, and mated in response to group female (and not male) behavior, we conclude that western gorillas used PC mating as a form of female competition, and not to confuse paternity or to obtain immediate benefits from the male, as suggested earlier. The male initiated copulations preferentially with females of high rank, rather than distinguishing between pregnant and cycling females. Therefore, PC mating appears to be a strategy by which high‐ranking pregnant females attempt to minimize male interest in other females, while reinforcing their own status and potentially delaying conception in others. These findings indicate that female‐mating competition is more important than considered earlier, and may be a factor in the evolution of nonconceptive mating in humans. Am. J. Primatol. 71:1011–1020, 2009. © 2009 Wiley‐Liss, Inc.
The impact of antipsychotic side effects on attitudes towards medication in people with schizophrenia and related disorders.

AIMS AND OBJECTIVES This research aimed to: (i) investigate the prevalence and perceived severity of antipsychotic side effects in people with schizophrenia and related disorders living in communities in Singapore; (ii) examine the relationship between antipsychotic variables (type, dose, route, prescription duration) and side effects; and (iii) examine the relationship between side effects and attitudes towards medication. BACKGROUND Antipsychotics are the mainstay treatment in schizophrenia and other psychotic disorders. However, antipsychotics are associated with a wide range of side effects, which potentially have adverse effects on patients' functioning. A lack of studies comparing the frequency of side effects and their associated levels of distress across multiple antipsychotics and different medication variables has been noted. Additionally, it is essential to assess patients' attitudes towards antipsychotics in relation to their experience of side effects. DESIGN A cross-sectional, non-experimental research design was used. METHOD A convenience sample of 96 adults with schizophrenia and related disorders on antipsychotic treatment and attending the hospital's outpatient clinic was recruited. Variables collected included antipsychotic type, dose, route, prescription duration and side effects, attitudes towards medication and demographic and clinical variables. They were analysed with descriptive statistics and correlational analyses. RESULTS Many participants experienced psychic (80·2%), extrapyramidal (69·8%) and miscellaneous side effects (61·5%). Side effects positively correlated with dose (p = 0·016) and negatively correlated with prescription duration (p = 0·014). Negative attitudes towards medication were positively correlated with side effects in general (p = 0·023), along with hormonal (p = 0·013) and psychic side effects (p = 0·008). CONCLUSION Findings revealed that majority of the participants experienced and were distressed over psychic, extrapyramidal and weight gain, which may be related to high doses and treatment duration. Additionally, patients experiencing psychic and hormonal side effects are at risk of developing negative attitudes towards medication. RELEVANCE TO CLINICAL PRACTICE Findings guide the development of appropriate nursing interventions that aim to alleviate side effects, reduce negative attitudes towards medication and prevent compliance problems.
MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma*

Background: Osteosarcoma (OS) is associated with loss of tumor suppressor p53 and increased Runx2. Results: Runx2 and p53 levels are inversely correlated in OS. miR-34c, which targets Runx2, is absent in OS and elevated by p53. Conclusion: p53, miR-34c, and Runx2 form a regulatory loop that is compromised in OS. Significance: RUNX2 could be targeted by miR-34c to prevent OS growth. Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3′-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.
Black and gold howler monkeys (Alouatta caraya) as sentinels of ecosystem health: patterns of zoonotic protozoa infection relative to degree of human–primate contact

Exponential expansion of human populations and human activities within primate habitats has resulted in high potential for pathogen exchange creating challenges for biodiversity conservation and global health. Under such conditions, resilient habitat generalists such as black and gold howler monkeys (Alouatta caraya) may act as effective sentinels to overall ecosystem health and alert us to impending epidemics in the human population. To better understand this potential, we examined noninvasively collected fecal samples from black and gold howler monkeys from remote, rural, and village populations in Northern Argentina. We examined all samples (n=90) for the zoonotic protozoa Cryptosporidium sp. and Giardia sp. via immunofluorescent antibody (IFA) detection. All samples were negative for Cryptosporidium sp. The prevalence of Giardia sp. was significantly higher at the rural site (67%) compared with the remote forest (57%) and village (40%) sites. A lack of Cryptosporidium sp. in all samples examined suggests that this pathogen is not a natural component of the howler parasite communities at these sites and that current land‐use patterns and livestock contact are not exposing Argentine howler monkeys to this pathogen. High prevalence of Giardia sp. at all sites suggests that howler monkeys may serve as a viable reservoir for Giardia. Significantly higher prevalence of Giardia sp. at the rural site, where primate–livestock contact is highest, suggests the presence of multiple Giardia clades or increased exposure to Giardia through repeated zoonotic transmission among nonhuman primates, livestock, and/or people. These results highlight the need for future research into the epidemiology, cross‐species transmission ecology, and clinical consequences of Giardia and other infectious agents not only in humans and livestock, but also in the wild animals that share their environments. Am. J. Primatol. 73:75–83, 2011. © 2010 Wiley‐Liss, Inc.
Spirometric parameters of judo training and inactive young men - measured compared to predicted values as one of wellness indicators

We wrześniu i październiku 2010 roku wykonano badania antropometryczne oraz spirometryczne w dwoch grupach mezczyzn. Pierwszą grupe stanowily osoby trenujące wyczynowo judo, drugą mlodziez szkolna – meska, deklarujący brak wyczynowej aktywności fizycznej. W obu grupach rozpietośc wiekowa badanych byla podobna. Uzyskane wyniki pokazaly, ze wśrod nieaktywnych mezczyzn zawartośc tkanki tluszczowej jest istotnie wieksza niz w grupie trenującej. Jednocześnie wskaźnik ruchomości klatki piersiowej, swobodna zyciowa pojemnośc, takze w przeliczeniu na jednostke masy ciala są istotnie wieksze u mezczyzn aktywnych fizycznie. U zawodnikow, jezeli wystepuje przyrost wskaźnika BMI, to odbywa sie on poprzez przyrost masy mieśniowej a nie ilości tluszczu. Wykazano, ze wskaźnik ruchomości klatki piersiowej obok parametrow spirometrycznych moze stanowic obiektywny miernik jakości zycia.
Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression*

Background: Maintaining bone architecture requires continuous generation of osteoblasts from osteoprogenitors. Results: EGFR signaling stimulates the expression of transcription factor EGR2 to promote osteoprogenitor proliferation and survival. Conclusion: EGFR-induced EGR2 expression is critical for osteoprogenitor maintenance and new bone formation. Significance: Understanding the mechanism of growth factor regulation of osteoprogenitor pool is crucial for designing a new anabolic strategy to treat bone-related diseases. Maintaining bone architecture requires continuous generation of osteoblasts from osteoprogenitor pools. Our previous study of mice with epidermal growth factor receptor (EGFR) specifically inactivated in osteoblast lineage cells revealed that EGFR stimulates bone formation by expanding the population of mesenchymal progenitors. EGFR ligands are potent regulators for the osteoprogenitor pool, but the underlying mechanisms are largely unknown. Here we demonstrate that activation of EGFR increases the number of osteoprogenitors by promoting cell proliferation and suppressing either serum depletion-induced or TNFα-induced apoptosis mainly through the MAPK/ERK pathway. Mouse calvarial organ culture revealed that EGF elevated the number of proliferative cells and decreased the number of apoptotic cells, which led to increased osteoblasts. Microarray analysis of MC3T3 cells, an osteoprogenitor cell line, revealed that EGFR signaling stimulates the expression of MCL1, an antiapoptotic protein, and a family of EGR transcription factors (EGR1, -2, and -3). The up-regulation of MCL1 and EGR2 by EGF was further confirmed in osteoprogenitors close to the calvarial bone surface. Overexpression of NAB2, a co-repressor for EGRs, attenuated the EGF-induced increase in osteoprogenitor number. Interestingly, knocking down the expression of EGR2, but not EGR1 or -3, resulted in a similar effect. Using inhibitor, adenovirus overexpression, and siRNA approaches, we demonstrate that EGFR signaling activates the MAPK/ERK pathway to stimulate the expression of EGR2, which in turn leads to cell growth and MCL1-mediated cell survival. Taken together, our data clearly demonstrate that EGFR-induced EGR2 expression is critical for osteoprogenitor maintenance and new bone formation.
Refining English Language Tests for University Admission: A Malaysian example

English has now become the lingua franca of much of technological, business and academic endeavours. Consequently, learning the English language is now seen as vital, especially at the university level where proficiency in the language has become a selection criterion. At present, the Malaysian University English Test (MUET) has been adopted by Malaysian public universities as an indicator of English language proficiency. A student’s overall result depends on all the four language components of the MUET and often determines the number and nature of the English language courses he or she has to attend at university. This study seeks to examine whether MUET is an accurate predictor of performance and success at university and how the MUET can be finetuned as an entry level English language test. It was carried out among 52 third year undergraduates of the Faculty of Educational Studies, Universiti Putra Malaysia, Serdang, Malaysia, admitted into the Teaching English as a Second Language (TESL) programme. The findings of the study do not offer conclusive evidence about the validity of MUET as a predictor of academic success. However, six models of various combinations of scores on language components on the MUET scores are examined in terms of their effectiveness in increasing the accuracy in selecting students for the TESL programme. The correlations obtained using these models indicate that the combination of various components of the MUET can be used to more accurately predict student achievement at tertiary level than the cumulative MUET score itself. The results of these correlations and their implications in using language tests as admission requirements in general are also discussed.
The Predictive Validity of Information From Clinical Practice Lessons: Experimental Evidence From Argentina

A growing number of teacher preparation programs require trainees to practice teaching. Yet, there is almost no evidence on whether the performance of individuals during clinical practice lessons predicts how they fare once they enter the school system. We address this question by taking advantage of the fact that an alternative pathway into teaching in Argentina requires admitted applicants to complete two weeks of clinical practice. We collect information both during clinical practice and the school year. During clinical practice, we measure the performance of teaching trainees using classroom observations and student surveys. During the school year, we measure their performance using classroom observations, student surveys, and principal surveys. We find that the overall performance of trainees during clinical practice predicts their overall performance during the school year, but this prediction is only statistically under certain model specifications. The performance of these individuals during clinical practice predicts their ratings on classroom observations during the school year. This relationship remains statistically significant even when we account for how trainees fare on the application and selection processes of the alternative pathway. We also find that the performance of trainees on a brief demonstration lesson, delivered during the selection process, predicts their performance on classroom observations during the school year. The predictive effect is smaller than that of clinical practice lessons, but it raises the question of whether the additional effort required to collect information during clinical practice is worth the improved predictive validity.
Analysis of the hydrogenotrophic microbiota of wild and captive black howler monkeys (Alouatta pigra) in palenque national park, Mexico

Intestinal methanogenesis is one of the major pathways for consumption of hydrogen produced by bacterial fermentation and is considered to affect the efficiency of host energy harvest; however, little information is available regarding the hydrogenotrophic pathways of nonhuman primates in the wild, in general, and of howler monkeys, in particular. Microbial fermentation of plant structural carbohydrates is an important feature in wild howlers owing to the high fiber and low available energy content of leaves, which make up the primary component of their diet. In contrast, captive howlers may consume greater quantities of fruits and vegetables that are higher in water, lower in fiber, and, along with commercial monkey chow commonly added to captive monkey diets, more readily digestible than the natural diet. In this study, we analyzed the composition of methanogens and sulfate‐reducing bacteria (SRB) from fecal samples of black howler monkeys (Alouatta pigra) in the wild and in captivity. The hydrogenotrophic microbiota of three groups of monkeys was evaluated by PCR‐denaturing gradient gel electrophoresis (DGGE) fingerprinting, small clone library construction, and quantitative real‐time PCR. Abundance of methanogens was lower than SRB in all howler monkey groups studied. DGGE banding patterns were highly similar within each wild and captive group but distinct among groups. Desulfovibrionales‐enriched DGGE showed reduced microbial diversity in the captive animals compared with their wild counterparts. Taken together, the data demonstrate that environmental or dietary changes of the host imposed by captivity likely influence the composition of intestinal hydrogenotrophs in black howler monkeys. Am. J. Primatol. 73:909–919, 2011. © 2011 Wiley‐Liss, Inc.
Differential Roles of the C and N Termini of Orai1 Protein in Interacting with Stromal Interaction Molecule 1 (STIM1) for Ca2+ Release-activated Ca2+ (CRAC) Channel Activation*

Background: STIM1-operated Orai1 channels mediate Ca2+ entry for T cell activation, but the gating mechanism remains elusive. Results: The C and N termini of Orai1 have differential roles in STIM1-triggered channel activation. Conclusion: The binding between STIM1 and the Orai1 C terminus docks STIM1 onto the Orai1 N terminus, leading to channel activation. Significance: This stepwise gating mechanism contributes to ER-PM crosstalk for Ca2+ entry, a fundamental process in cell biology. The entry of extracellular Ca2+, which is mediated by Ca2+ release-activated Ca2+ (CRAC) channels, is essential for T cell activation and the normal functioning of other immune cells. Although the molecular components of CRAC channels, the Orai1 pore-forming subunit and the STIM1-activating subunit have been recently identified, the gating mechanism by which Orai1 channels conduct Ca2+ entry upon Orai1-STIM1 interaction following Ca2+ store release remains elusive. Herein, we show that C-terminal truncations or point mutations prevented Orai1 from binding to STIM1 and subsequent channel opening. In contrast, an Orai1 mutant with an N-terminal truncation interacted with but failed to be activated by STIM1. Moreover, Orai1 channels with C-terminal disruption, but not N-terminal truncation, could be gated by fused functional domains of STIM1. Interestingly, the channel activities of Orai1 mutants carrying either an N-terminal or a C-terminal truncation were restored by a methionine mutation at the putative gating hinge, the conserved Gly-98 site in the first transmembrane segment (TM1) of Orai1. Collectively, these results support a stepwise gating mechanism of STIM1-operated Orai1 channels; the initial binding between STIM1 and the C terminus of Orai1 docks STIM1 onto the N terminus of Orai1 to initiate conformational changes of the pore-lining TM1 helix of Orai1, leading to the opening of the channel.