Adaptive HIV-1 evolutionary trajectories are constrained by protein stability

Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistance may be conferred either by a single mutation or a concerted set of mutations. The involvement of multiple mutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1's Pol protein, and traced the evolutionary trajectories leading to mutations associated with drug resistance. Using contemporary and ancestral sequences we modelled the effects of mutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although the majority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1's evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistant mutations, for example, associated with escape from the immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents a major constraining factor to the evolution of HIV-1

A study of Neo-Humanist Kindergarten's Physical Environment in Supporting Social Skills

The main focus of this study was to examine how a kindergarten’s physical environment supports the social skills of negotiation, problem-solving and fairness of children aged five to seven-year-olds. The study was carried out in a private English neo-humanist kindergarten using qualitative research method, and the data was collected by observing seven children in ten participant observations during free play indoors and outdoors. Data was analysed using interpretative content analysis approach in order to answer the research question of how a kindergarten setting and play materials support children’s social skills. The findings show that kindergarten play props and physical environment support children social skills as they exhibit sufficient level of social skills in interaction with one another indoors and outdoors. However, few anti-social behaviours were also recorded during the use of some play props provided. Findings also emphasize the important role of an adult in the physical environment as propounded by social-constructivists’ theory. In conclusion, recommendations were made on how the practitioners could widen the physical environment to include more play areas and types of play props that could also be introduce to further support children’s skills of negotiation, fairness and problem-solving. Keywords: Early childhood education, Physical environment, Social skills, Play props, Neo-humanist educationNeo-humanistisen päiväkodin fyysinen ympäristö sosiaalisten taitojen tukijana Tämän tutkimuksen pääasiallisena painopisteenä oli tutkia, kuinka päiväkodin fyysinen ympäristö tukee 5-7-vuotiaiden lasten sosiaalisia taitoja, erityisesti neuvottelu- ja ongelmanratkaisutaitoja sekä reiluutta. Tutkimus toteutettiin yksityisessä, englanninkielisessä neo-humanistisessa päiväkodissa hyödyntäen laadullista tutkimusotetta. Aineisto kerättiin observoimalla seitsemää lasta vapaan leikin aikana sekä päiväkodin sisä –että ulkotiloissa. Kaikilla kymmenellä aineistonkeruukerralla käytimme osallistuvaa havainnointia tutkimusmetodina. Lopuksi aineisto analysoitiin hyödyntäen tulkinnallista sisällönanalyysia, mikä mahdollisti vastaamisen tutkimuskysymykseen kuinka päiväkotimiljöö sekä leikkirekvisiitat tukevat lasten sosiaalisia taitoja. Tutkimuksen tulokset osoittavat, että päiväkodin leikkirekvisiitat sekä fyysinen miljöö tukevat lasten sosiaalisia taitoja silloin, kun lapset ilmentävät riittävän tasoisia sosiaalisia taitoja vuorovaikutuksessa toisten lasten kanssa niin sisä- että ulkotiloissa. Joidenkin leikkirekvisiittojen parissa havainnointiin myös epäsosiaalista käyttäytymistä, jolloin tunnistettavissa oli puutteellisia sosiaalisia taitoja.Tulokset korostavat myös sitä, että aikuisella on tärkeä rooli fyysisessä varhaiskasvatusympäristössä, jota myös sosiaalis-konstruktiivinen näkemys puoltaa. Kehityssuositukset kohdennettiin fyysiseen varhaiskasvatusympäristöön; varhaiskasvatusopettajat voivat laajentaa fyysistä ympäristöä liittämällä mukaan enemmän leikkinurkkauksia ja erilaisia leikkirekvisiittoja, joiden tarkoitus on edesauttaa sosiaalisten taitojen, kuten neuvottelu- ja ongelmanratkaisutaitojen sekä reiluuden tukemista. Avainsanat: Varhaiskasvatus, Fyysinen ympäristö, Sosiaaliset taidot, Leikkirekvisiitat, Neo-humanistinen kasvatu

Dopamiinin hapettumisen lukija-anturirajapinta 65 nm CMOS teknologialla

Sensing and monitoring of neural activities within the central nervous system has become a fast-growing area of research due to the need to understand more about how neurons communicate. Several neurological disorders such as Parkinson’s disease, Schizophrenia, Alzeihmers and Epilepsy have been reported to be associated with imbalance in the concentration of neurotransmitters such as glutamate and dopamine [1] - [5]. Hence, this thesis proposes a solution for the measurement of dopamine concentration in the brain during neural communication. The proposed design of the dopamine oxidation readout sensor interface is based on a mixed-signal front-end architecture for minimizing noise and high resolution of detected current signals. The analog front-end is designed for acquisition and amplification of current signals resulting from oxidation and reduction at the biosensor electrodes in the brain. The digital signal processing (DSP) block is used for discretization of detected dopamine oxidation and reduction current signals that can be further processed by an external system. The results from the simulation of the proposed design show that the readout circuit has a current resolution of 100 pA and can detect minimum dopamine concentration of 10 μMol based on measured data from novel diamond-like carbon electrodes [6]. Higher dopamine concentration can be detected from the sensor interface due to its support for a wide current range of 1.2 μA(±600 nA). The digital code representation of the detected dopamine has a resolution of 14.3-bits with RMS conversion error of 0.18 LSB which results in an SNR of 88 dB at full current range input. However, the attained ENOB is 8-bits due to the effect of nonlinearity in the oscillator based ADC. Nonetheless, the achieved resolution of the readout circuit provides good sensitivity of released dopamine in the brain which is useful for further understanding of neurotransmitters and fostering research into improved treatments of related neurodegenerative diseases.Keskushermoston aktiivisuuden havainnointi ja tarkkailu on muodostunut tärkeäksi tutkimusalaksi, sillä tarve ymmärtää neuronien viestintää on kasvanut. Monien hermostollisten sairauksien kuten Parkinsonin taudin, skitsofrenian, Alzheimerin taudin ja epilepsian on huomattu aiheuttavan muutoksia välittäjäaineiden, kuten glutamaatin ja dopamiinin, pitoisuuksissa [1] - [5]. Aiheeseen liittyen tässä työssä esitetään ratkaisu dopamiinipitoisuuden mittaamiseksi aivoista. Esitetty dopamiinipitoisuuden lukijapiiri perustuu sekamuotoiseen etupäärakenteeseen, jolla saavutetaan matala kohinataso ja hyvä tarkkuus signaalien ilmaisemisessa. Suunniteltu analoginen etupää kykenee lukemaan ja vahvistamaan dopamiinipitoisuuden muutosten aiheuttamia virran muutoksia aivoihin asennetuista elektrodeista. Digitaalisen signaalinkäsittelyn avulla voidaan havaita dopamiinin hapettumis-ja pelkistymisvirtasignaalit, ja välittää ne edelleen ulkoisen järjestelmän muokattavaksi. Simulaatiotulokset osoittavat, että suunniteltu piiri saavuttaa 100 pA virran erottelukyvyn. Simuloinnin perustuessa hiilipohjaisiin dopamiinielektrodeihin piiri voi havaita 10 μMol dopamiinipitoisuuden [6]. Myös suurempia dopamiinipitoisuuksia voidaan havaita, sillä etupäärajapinta tukee 1.2 μA(±600 nA) virta-aluetta. Digitaalinen esitysmuoto tukee 14.3 bitin esitystarkkuutta 0.18 bitin RMS virheellä saavuttaen 88 dB dynaamisen virta-alueen. Saavutettu ENOB (tehollinen bittimäärä) on kuitenkin 8 bittiä oskillaattoripohjaisen ADC:n (analogia-digitaalimuuntimen) epälineaarisuuden takia. Saavutettu tarkkuus tuottaa hyvän herkkyyden dopamiinin havaitsemiseksi ja hyödyttää siten välittäjäainetutkimusta ja uusien hoitomuotojen kehittämistä hermostollisiin sairauksiin

The Nature of Payment Problems in the New Zealand Construction Industry

Delay and loss of payment is a serious problem in the construction industry of many countries. These affect the cash flow of contractors which is critical to meeting their financial obligations. Payment defaults by the principal leads to insolvency of contractors and in turn other parts of the project chain. In recognition of some of these problems, most countries have established payment-specific construction industry legislation and other contractual measures to mitigate the problems, but nevertheless the problem persists. In this context, the paper examines the nature of payment problems in the construction industry in New Zealand. It is part of a larger study, that seeks solutions to payment losses in the construction industry.The study uses two approaches; an analysis of liquidators’ reports, and an analysis of court cases involving payment disputes to determine the magnitude of payment problems on construction parties. The findings are presented using simple descriptive and interpretive analyses. The study finds that trade creditors are impacted negatively (payment delays and losses) by the liquidation of property developers, general construction and construction trade companies. 75% of trade creditors are unable to be paid fully by these categories of construction companies after liquidation proceedings. Liquidation proceedings take an average 18 months before they are finalised. The analysis of court cases found that 80% of payment disputes are between principals and contractors; with considerably significant percentage of disputes resulting in outright loss of payments. Only 40% of the cases are successful, in which case claimants are able to fully recover the amount in dispute. Payment losses are more prevalent in liquidation than delays and unlike in legal disputes, there is no security for those losses. The study finds that construction parties use remedies contained in the security of payment provisions within standard conditions of contract, and legislative documents

Managing Gas Flaring and Allied Issues in the Oil and Gas Industry: Reflections on Nigeria

The level of gas flaring attributable to the international oil and gas industry is without a doubt very significant. This realization, has led to a global reaction to reduce gas flaring volumes in the light of the adverse environmental, economic and social consequences connected with the high incidence of gas flaring. Hence, the approach being adopted to achieve a manageable level of gas flaring is as diverse as the respective countries that contend with this peculiar problem. The direction thus far, has been to address the gas flaring dilemma on a national, regional and international platform. Gas flaring cannot be construed in isolation, and as a consequence its consideration, has also brought to the fore matters related to environmental protection. Moreover, gas flaring has been identified as a process that damages the ozone layer, and thus contributing to escalating the global warming phenomenon. Amongst others, this notable finding has further stimulated domestic and international initiatives aimed at curbing the adverse effects of gas flaring. In Nigeria’s case, there is an apparent incentive to mitigate the incidence of gas flaring in view of; the country’s heavy reliance on oil and gas revenues, as well as the identifiable policy adjustments that need to be achieved on a sustained basis

Toxicology of solvent extract and fractions of Alstonia boonei (DC.) Wild stem bark in Rats

Introduction: Toxic effects arising from the use of medicinal herbs have been frequently overshadowed by the therapeutic efficacy of phytomedicines. This study was carried out to assess the safety of extract and fractions of Alstonia boonei (de wild) stem bark, popularly used in the treatment of malaria especially in Africa. Methods: Rats were orally exposed to different doses (200 and 400 mg/kg body weight) of methanol extract (ME), n-hexane (HF), chloroform (CF), ethylacetate (EF) and aqueous fractions (AF) of A. boonei for 7 days. Furthermore, 10 mg/ kg body weight (bw) of chloroquine (CQN) was administered as standard drug for 7 days while, 5% tween 80 (TT) and distilled water (TW) were administered as control for 7 days. Group I (treatment group) was sacrificed after 7 days while group II (recovery group) was left for 21 days to recover and thereafter sacrificed. The effects of treatment and recovery were analyzed using serum biomarkers, hematological parameters and tissue histopathological evaluation. Results: There was reduction in hematological parameters after 7 days but recovered after 21 days. There was also increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), after 7 days. Compared to TW and TT treated groups, histopathological scores of liver and kidney were critical for all groups at 400 mg/kg bw after 21 days. Conclusion: The animals did not fully recover after 21 days, suggesting that 400 mg/kg bw of extract and fractions of A. boonei were both hepatotoxic and nephrotoxic. Hence this plant should be used with caution

Annulment of Oil Licences in Nigeria’s Upstream Petroleum Sector: A Legal Critique of the Costs and Benefits

Owing to various reasons, tenable and untenable, successive governments in Nigeria have annulled licenses duly granted to identifiable upstream petroleum operators. With due sense of circumspect, when irregularities manifest in the process and the grant of substantive licences, such does not vest in the government an unfettered right to annul the licence. There are evidences of such occurrence in spite of established procedures regulating annulments, commonly referred to as revocation or cancellation. This paper is a critique of the annulment of oil licenses and the associated contractualregulatory dimensions. The validity of the Federal Government’s actions also comes to the fore, particularly in the light of renewed drive to attract investments into the upstream sector. Thus, as some benefits are accruable to the players, it is also important to appraise the consequential costs attributable to undue annulment of oil licenses. The paper adopts a descriptive analytical method of available facts, expounds requisite statutory provisions and utilizes judicial precedents to highlight the context of the study. It is imperative that the Federal Government adheres to established procedures on oil license annulment, as a contrary posture will amount to several negative outcomes