The acquisition of se-verbs in Serbian as L1 (Usvajanje glagola sa klitikom se u srpskom jeziku kao maternjem)

Studije koje se bave usvajanjem maternjeg jezika nam pružaju uvid u način na koji deca percipiraju odnos između ekstralingvističke situacije/aktivnosti/događaja i učesnika u datoj situaciji/aktivnosti/događaju, kao i u način na koji ga verbalizuju kao odnos između glagola i njegovih argumenata na jezičkom nivou. To prenošenje na jezički nivo nas informiše o toku usvajanja jezika. Kako glagoli zauzimaju centralnu poziciju u klauzi, izučavanje argumentske strukture se već godinama nalazi u fokusu psiholingvističkih istraživanja. Postojeće studije pokazuju da se povratni glagoli usvajaju prilično rano (Snyder–Hyams, & Crisma, 1995; Snyder–Hyams, 2015). Ipak, neka istraživanja su došla do zaključka da deca imaju poteškoća sa pomeranjem unutrašnjeg argumenta na položaj subjekta (engl. A-chain Deficit Hypothesis; Borer–Wexler, 1987; Babyonyshev–Fein–Ganger–Pesetsky, & Wexler, 2001), dok rezultati drugih eksperimenata ukazuju na problem sa usvajanjem glagola koje karakteriše alternirajuća tranzitivnost (glagola koji mogu biti i tranzitivni i intranzitivni) (Brooks–Tomasello, 1999). Cilj ove disertacije je bio da ispita uspeh dece u produkciji različitih vrsta glagola koji se javljaju sa klitikom se: pravih povratnih glagola (npr. oblačiti se), leksički povratnih glagola (npr. penjati se), uzajamno-povratnih glagola (npr. grliti se), leksički uzajamno-povratnih glagola (npr. svađati se) i anti-kauzativnih glagola (npr. polomiti se). Nijedan od ovih tipova glagola nije sintaksički jednostavan, pošto ni kod jednog nije prisutno kanoničko povezivanje tematskih uloga agensa i pacijensa sa sintaksičkim funkcijama subjekta i objekta. Ipak, inicijalna hipoteza je bila da se pravi povratni glagoli usvajaju pre uzajamno-povratnih i anti-kauzativnih glagola, jer se kod njih dve tematske uloge (agensa i pacijensa), realizovane u vidu koreferencijalnih argumenata, preslikavaju na funkciju subjekta na nivou sintakse. Kod uzajamno-povratnih glagola su prisutna dva nekoreferencijalna argumenta, koja istovremeno obavljaju i funkciju subjekta i funkciju objekta, dok anti-kauzativne glagole karakteriše sintaksički kompleksan proces derivacije iz tranzitivnog glagola, uz brisanje spoljašnjeg argumenta. Drugi cilj ove teze je bilo poređenje morfosintaksički izvedenih (pravih) oblika i leksičkih oblika povratnih i uzajamno povratnih glagola. Leksički povratni i uzajamno-povratni glagoli nisu zamenljivi tranzitivnim glagolima, kao što je to slučaj sa pravim povratnim i uzajamno-povratnim glagolima, što bi moglo da doprinese njihovoj uspešnijoj produkciji. Naposletku, razmotrili smo kakve posledice rezultati istraživanja imaju na opis statusa i funkcije klitike se u srpskom jeziku. Nakon sprovođenja pilot istraživanja, čija je svrha bila da se proveri kako deca reaguju na stimuluse, i u skladu s tim izvrše neophodne korekcije, deca su prvi put testirana u februaru 2019. godine, a zatim iznova devet meseci kasnije. U oba eksperimenta je učestvovalo ukupno 60 ispitanika iz 3 starosne grupe (od otprilike tri, četiri i pet godina starosti – po 20 ispitanika u svakoj). Tehnika prikupljanja podataka je bila zadatak elicitirane produkcije uz korišćenje unapred pripremljenih vizuelnih stimulusa (crteža), a od dece se tražilo da imenuju navedene radnje. Broj testiranih glagola iz svake grupe je bio jednak (šest glagola po grupi, ukupno trideset ciljnih glagola). Podaci su statistički obrađeni analizom iz porodice Mešovitih linearnih modela. U prvom delu istraživanja, ispitano je koji se od pet vrsta glagola produkuju sa većim uspehom od ostalih u svakoj od tri starosne grupe. U drugom delu istraživanja, testiran je porast u produkciji pojedinačnih vrsta glagola u tri starosne grupe. Nezavisne varijable u istraživanju su bile vrsta glagola i uzrast dece. Zavisna varijabla je bila produkcija ciljnih odgovora po tipovima glagola (unutar starosne grupe i između starosnih grupa). Dužina i frekvencija glagola su takođe testirane kao kovarijable. Rezultati dobijeni u prvom eksperimentu su pokazali da deca najtačnije produkuju leksički povratne glagole, te prave povratne glagole. S druge strane, čini se da produkcija pravih uzajamno-povratnih, leksički uzajamno-povratnih, kao i anti-kauzativnih glagola kasni, što je i bilo očekivano, s obzirom na veću kompleksnost ovih glagola. Isti eksperiment je ponovljen u decembru 2019. Rezultati su potvrdili prethodne zaključke, iako je produkcija svih vrsta glagola bila mnogo uspešnija, uključujući i one koji su se pokazali teškim, što je rezultovalo time da neke razlike u produkciji različitih tipova glagola unutar, kao i između starosnih grupa, više nisu bile prisutne. Opšte uzevši, rezultati istraživanja ukazuju na to da se povratni glagoli usvajaju pre uzajamno-povratnih i anti-kauzativnih glagola, što potvrđuje inicijalnu hipotezu. Kada je reč o statusu klitike se, rezultati ove studije su u skladu sa prethodnim istraživanjima (Ivić, 1961–1962; Piper et al., 2005; Arsenijević, 2011; Reinhart–Siloni, 2003), što nas dovodi do zaključka da klitika se i povratna zamenica sebe imaju različitu distribuciju u jezičkoj produkciji glagola sa klitikom se, te se stoga predlaže da bi klitiku se pre trebalo tretirati kao odvojenu morfemu, nego kao skraćeni oblik povratne zamenice

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene. Keyword: PIK3CA; 2OG; OGDH; TCA cycle; glycolysisDamon Runyon Cancer Research Foundation (HHMI Fellowship

The potential role of lycopene for the prevention and therapy of prostate cancer: From molecular mechanisms to clinical evidence

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have linked increased lycopene consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that lycopene not only enhances the antioxidant response of prostate cells, but that it is even able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, there is still no clearly proven clinical evidence supporting the use of lycopene in the prevention or treatment of prostate cancer, due to the only limited number of published randomized clinical trials and the varying quality of existing studies. The scope of this article is to discuss the potential impact of lycopene on prostate cancer by giving an overview about its molecular mechanisms and clinical effects. © 2013 by the authors; licensee MDPI, Basel, Switzerland

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study

Background: To contribute to the WHO initiative, VISION 2020: The Right to Sight, an assessment of global vision impairment in 2020 and temporal change is needed. We aimed to extensively update estimates of global vision loss burden, presenting estimates for 2020, temporal change over three decades between 1990–2020, and forecasts for 2050. Methods: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. Only studies with samples representative of the population and with clearly defined visual acuity testing protocols were included. We fitted hierarchical models to estimate 2020 prevalence (with 95% uncertainty intervals [UIs]) of mild vision impairment (presenting visual acuity ≥6/18 and <6/12), moderate and severe vision impairment (<6/18 to 3/60), and blindness (<3/60 or less than 10° visual field around central fixation); and vision impairment from uncorrected presbyopia (presenting near vision <N6 or <N8 at 40 cm where best-corrected distance visual acuity is ≥6/12). We forecast estimates of vision loss up to 2050. Findings: In 2020, an estimated 43·3 million (95% UI 37·6–48·4) people were blind, of whom 23·9 million (55%; 20·8–26·8) were estimated to be female. We estimated 295 million (267–325) people to have moderate and severe vision impairment, of whom 163 million (55%; 147–179) were female; 258 million (233–285) to have mild vision impairment, of whom 142 million (55%; 128–157) were female; and 510 million (371–667) to have visual impairment from uncorrected presbyopia, of whom 280 million (55%; 205–365) were female. Globally, between 1990 and 2020, among adults aged 50 years or older, age-standardised prevalence of blindness decreased by 28·5% (–29·4 to −27·7) and prevalence of mild vision impairment decreased slightly (–0·3%, −0·8 to −0·2), whereas prevalence of moderate and severe vision impairment increased slightly (2·5%, 1·9 to 3·2; insufficient data were available to calculate this statistic for vision impairment from uncorrected presbyopia). In this period, the number of people who were blind increased by 50·6% (47·8 to 53·4) and the number with moderate and severe vision impairment increased by 91·7% (87·6 to 95·8). By 2050, we predict 61·0 million (52·9 to 69·3) people will be blind, 474 million (428 to 518) will have moderate and severe vision impairment, 360 million (322 to 400) will have mild vision impairment, and 866 million (629 to 1150) will have uncorrected presbyopia. Interpretation: Age-adjusted prevalence of blindness has reduced over the past three decades, yet due to population growth, progress is not keeping pace with needs. We face enormous challenges in avoiding vision impairment as the global population grows and ages

Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study

Background: Many causes of vision impairment can be prevented or treated. With an ageing global population, the demands for eye health services are increasing. We estimated the prevalence and relative contribution of avoidable causes of blindness and vision impairment globally from 1990 to 2020. We aimed to compare the results with the World Health Assembly Global Action Plan (WHA GAP) target of a 25% global reduction from 2010 to 2019 in avoidable vision impairment, defined as cataract and undercorrected refractive error. Methods: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. We fitted hierarchical models to estimate prevalence (with 95% uncertainty intervals [UIs]) of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (<3/60 or less than 10° visual field around central fixation) by cause, age, region, and year. Because of data sparsity at younger ages, our analysis focused on adults aged 50 years and older. Findings: Global crude prevalence of avoidable vision impairment and blindness in adults aged 50 years and older did not change between 2010 and 2019 (percentage change −0·2% [95% UI −1·5 to 1·0]; 2019 prevalence 9·58 cases per 1000 people [95% IU 8·51 to 10·8], 2010 prevalence 96·0 cases per 1000 people [86·0 to 107·0]). Age-standardised prevalence of avoidable blindness decreased by −15·4% [–16·8 to −14·3], while avoidable MSVI showed no change (0·5% [–0·8 to 1·6]). However, the number of cases increased for both avoidable blindness (10·8% [8·9 to 12·4]) and MSVI (31·5% [30·0 to 33·1]). The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7–18·0]), followed by glaucoma (3·6 million cases [2·8–4·4]), undercorrected refractive error (2·3 million cases [1·8–2·8]), age-related macular degeneration (1·8 million cases [1·3–2·4]), and diabetic retinopathy (0·86 million cases [0·59–1·23]). Leading causes of MSVI were undercorrected refractive error (86·1 million cases [74·2–101·0]) and cataract (78·8 million cases [67·2–91·4]). Interpretation: Results suggest eye care services contributed to the observed reduction of age-standardised rates of avoidable blindness but not of MSVI, and that the target in an ageing global population was not reached. Funding: Brien Holden Vision Institute, Fondation Théa, The Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg

Regulatory considerations applicable to manufacturing of human placenta-derived mesenchymal stromal cells (MSC) used in clinical trials in Australia and comparison to USA and European regulatory frameworks

Independent development of regulatory frameworks in Australia, Europe and the USA has led to differences in their regulatory approach to biologics (or biologicals). Some of these were favourable for the conduct of early clinical trials (i.e. TGA CTN and CTX). Others have been affected by external factors (i.e. UK membership in the EU) or have expanded their scope (i.e. CBER emergence within the FDA). Recently efforts have been made to harmonise the three frameworks via joint guidances to industry and researchers and memoranda of understanding and cooperation among the regulatory bodies from the regions. We present our own experience in manufacturing and use of human placenta-derived mesenchymal stromal cells (hpMSC) in phase 1 clinical trials conducted in Australia according to the new Biologicals Framework established by Therapeutic Goods Administration (TGA) as from 1 July 2011. We also present similarities and differences with some other regulatory frameworks (USA and EU) that may be of interest to us in the future