Allosteric Modulation of the HIV-1 gp120-gp41 Association Site by Adjacent gp120 Variable Region 1 (V1) N-Glycans Linked to Neutralization Sensitivity

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/ or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and Cterminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn136 in V1 (T138N mutation) in
conjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N139INN sequence, which ablates the overlapping Asn141-Asn142-Ser-Ser potential N-linked glycosylation sequons in
V1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu593, Trp596 and Lys601. The 136 and/or 142
glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120-
gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb selection.

An explanation of capital structure of China's listed property firms

Purpose– The purpose of this paper is to investigate the determinants of the capital structure of listed property firms in China.Design/methodology/approach– The study is based on quantitative methods such as dynamic panel data models and a panel data set containing financial and accounting data for all listed property companies from 2006 to 2010 in China.Findings– The findings confirm that the state-own shares, the fixed asset values, the total size of assets and profitability have a positive and significant impact on the leverage ratio of listed property firms in China. The negative impact of the tax shields and the currency ratio, and significant impact of state-own shares on capital structure cannot be explained by existing capital structure theory but the unique property market regulation environment and market conditions in China.Research limitations/implications– The findings confirm the applicability of trade-off theory (except for the correlation between leverage and the tax shield) on property companies in China. They also highlight the importance of government policies and special market conditions in explaining the financing behaviour of property companies in transaction countries like China.Practical implications– Complimentary policies should be established along with property market restriction policies to offset their unequal negative effect on property companies with less state-owned shares. Furthermore, government should invest efforts to eliminate the discrimination credit treatment of banks against property companies with non-existent or few state-owned shares.Originality/value– The special financial behaviour of China's property firms and the unique financial and property market conditions highlight the necessity of researching the capital structure of listed property firms in China. However, most of the existing literature focuses on the company financial behaviour in developed countries, and very few studies have been done concerning property firms’ financing behaviour in emerging economies such as China, and this research prospects to fill this blank.

Determinants of mastitis in women in the CASTLE study: a cohort study

BACKGROUND: Mastitis is an acute, debilitating condition that occurs in approximately 20 % of breastfeeding women who experience a red, painful breast with fever. This paper describes the factors correlated with mastitis and investigates the presence of Staphylococcus aureus in women who participated in the CASTLE (Candida and Staphylococcus Transmission: Longitudinal Evaluation) study. The CASTLE study was a prospective cohort study which recruited nulliparous women in late pregnancy in two maternity hospitals in Melbourne, Australia in 2009-2011.

METHODS: Women completed questionnaires at recruitment and six time-points in the first eight weeks postpartum. Postpartum questionnaires asked about incidences of mastitis, nipple damage, milk supply, expressing practices and breastfeeding problems. Nasal and nipple swabs were collected from mothers and babies, as well as breast milk samples. All samples were cultured for S. aureus. "Time at risk" of mastitis was defined as days between birth and first occurrence of mastitis (for women who developed mastitis) and days between birth and the last study time-point (for women who did not develop mastitis). Risk factors for incidence of mastitis occurring during the time at risk (Incident Rate Ratios [IRR]) were investigated using a discrete version of the multivariable proportional hazards regression model.

RESULTS: Twenty percent (70/346) of participants developed mastitis. Women had an increased risk of developing mastitis if they reported nipple damage (IRR 2.17, 95 % CI 1.21, 3.91), over-supply of breast milk (IRR 2.60, 95 % CI 1.58, 4.29), nipple shield use (IRR 2.93, 95 % CI 1.72, 5.01) or expressing several times a day (IRR 1.64, 95 % CI 1.01, 2.68). The presence of S. aureus on the nipple (IRR 1.72, 95 % CI 1.04, 2.85) or in milk (IRR 1.78, 95 % CI 1.08, 2.92) also increased the risk of developing mastitis.

CONCLUSIONS: Nipple damage, over-supply of breast milk, use of nipple shields and the presence of S. aureus on the nipple or in breast milk increased the mastitis risk in our prospective cohort study sample. Reducing nipple damage may help reduce maternal breast infections.

Living alone and living together: their significance for well-being

Differential rates of demographic change between the developed and developing nations contribute to disparate living arrangements and contrasting cultural understandings of living together and alone. Among some cohorts in the developed world, who can afford it, living alone is seen as a lifestyle choice and representative of independence, thus not compromising of wellbeing. In some contexts living arrangements have minimal impact on wellbeing. However, in parts of the developing world, and among other cohorts in developed countries, living alone represents despair, abandonment and loneliness leading to diminished wellbeing. Overriding this cultural difference is the unambiguous population level data from across the world showing that intimate partnerships, particularly marriage, provide a protective shield against low personal wellbeing scores. The jury is still out on whether this protective effect necessarily involves cohabitation. The current rise in living- apart-together relationships and the possible future trend of living together virtually, through second life and other digital media, raises further questions about the nexus between living arrangements and wellbeing.

Addressing the curious black spot that is the separation between the principle of legality and sentencing

The principle of legality has evolved into a clear and entrenchedjurisprudential mechanism for protecting common law rights and freedoms. It operates as a shield to preserve the scope of application of fundamental rights and fre edoms. In recent years it has been increasingly applied by the courts to limit the scope of legislative provisions which potentially impinge on human rights and fundamental freedoms. Yet there is one domain where the principle of legality is conspicuously absent: sentencing. Ostensibly, this is paradoxical. Sentencing is the realm where the legalsystem operates in its most coercive manner against individuals. In thisarticle, we argue that logically the principle of legality has an importantrole in the sentencing system given the incursions by criminal sanctionsinto a number of basic rights, including the right to liberty, the freedom ofassociation and the deprivation of property. By way of illustration, we setout how the principle of legality should apply to the interpretation of keystatutory provisions. To this end, we argue that the objectives of generaldeterrence and specifi c deterrence should have less impact in sentencing. It is also suggested that judges should be more reluctant to send offenders with dependants to terms of imprisonment. Injecting the principle of legality into sentencing law and practice would result in the reduction in severity of a large number of sanctions, thereby reducing the frequency and extent to which the fundamental rights of offenders are violated. The methodology set out in this article can be applied to alter the operation of a number of legislative sentencing objectives and rules.

Women’s attitudes towards children and motherhood: a predictor of future childlessness?

Pronatalism expects and presumes that all women will be mothers, and stereotypes, stigmatises and excludes those who fail to conform. Yet, within the context of pronatalism, little is known about women without children’s attitudes towards motherhood, and their subsequent childbearing. This study aimed to determine if women’s attitudes towards children and motherhood predicted future motherhood status, using data from the Negotiating the Life Course Study. Women 18 years and over at Wave 1, who did not have children, were included in the analysis (n = 122). Logistic regression was used to predict motherhood status at Wave 4 based on attitudes at Wave 1. A positive attitude toward the importance of children in one’s life increased the likelihood of future motherhood, while believing children negatively impact on freedom increased the likelihood of not future childlessness. Findings also suggested that attitudes relating to the burden of children, or the impact of children on a woman’s career, are similar for those who do and do not become mothers. Women’s attitudes towards children and motherhood may be a poor predictor of future childlessness. This study counters some of the negative attitudinal stereotypes towards childless women in a pronatalist society.

Anti-cancer natural products inducing cross-talk between apoptosis and autophagy mutual proteins to regulate cancer cell death: design of future green anticancer therapies.

The present letter concerns anti-cancer natural products inducing cross-talk between apoptosis and autophagy mutual proteins to regulate cancer cell death for future cancer green therapeutic approaches. The course of cancer advancement has always been attributed to the defectiveness in cell death mechanisms (Du et al., 2013; Hematulin et al., 2014). These defects act as a shield in protecting tumor cells from drugs and therapies, all at the same time, maintaining a longer life span and prompting their dispersion procedures. Autophagy and apoptosis safeguards cells from cellular damages and maintains proliferation and homeostasis by deporting outgrowth and controlling differentiation of pernicious cells. The autophagic proteins are conventionally found in hindering apoptosis whereas vice versa accounts had been reported for apoptotic-intermediates in preventing autophagic responses.