The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors

CYP51 (Erg11) belongs to the cytochrome P450 monooxygenase (CYP) superfamily and mediates a crucial step of the synthesis of ergosterol, which is a fungal-specific sterol. It is also the target of azole drugs in clinical practice. In recent years, researches on fungal CYP51 have stepped into a new stage attributing to the discovery of crystal structures of the homologs in Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. This review summarizes the functions, structures of fungal CYP51 proteins, and the inhibitors targeting these homologs. In particular, several drug-resistant mechanisms associated with the fungal CYP51s are introduced. The sequences and crystal structures of CYP51 proteins in different fungal species are also compared. These will provide new insights for the advancement of research on antifungal agents

Survivin-based recombinant overlapping peptides induce t lymphocyte cytotoxicity and prolong the survival in in vivo melanoma model

Anti-cancer vaccination emerged as a promising and cost-effective immunotherapy, but the lack of immunogenicity has hindered the success of therapeutic vaccine development. To address this issue and improve therapeutic efficacy, this study presents the examination of recombinant overlapping peptides (ROP) based on the tumor-associated antigen, survivin, on in vivo immunogenicity and anti-tumor efficacy using a melanoma C57/BL mouse model. Results show that ROPs induce a remarkable 46.5% cytotoxic activity mediated by activated cytotoxic T lymphocytes, compared to only 3% in wild-type (WT) survivin protein. Additionally, ROPs significantly reduce tumor size by over 500 mm3 and prolong survival rates in mice with zero deaths in the first 17 days and 30% survival at the end of day 23, while no mice immunized with WT survivin protein survive beyond day 20. ROPs combined with anti-4-1BB agonists lead to additional tumor size reduction by 500 mm3 and 70% survival on day 23. These findings underscore the importance of survivin as a trigger for tumor-restricting immunity and provide therapeutic evidence of ROPs' anti-tumor potential, especially when combined with other immunostimulants, such as anti-4-1BB agonists. ROPs and adjuvant immunostimulants represent a potent vaccine strategy for therapeutic purposes, increasing vaccine immunogenicity and improving survival against cancer

Effect of Nicotinamide Against Candida albicans

Nicotinamide (NAM) has a long history in clinical applications and can be safely used for treating various diseases. In recent years, NAM was found to exhibit antimicrobial activities, inhibiting the growth of Plasmodium falciparum, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). Here we investigated the activity of NAM against Candida albicans, one of the most prevalent human fungal pathogens. Our results showed that NAM exhibited significant antifungal activity against C. albicans, including fluconazole-resistant isolates. NAM could also effectively suppress biofilm formation. In addition, NAM exhibited antifungal activity against non-Candida albicans species and Cryptococcus neoformans. Combination of NAM and fluconazole showed an even strong antifungal activity. The antifungal activity of NAM was further confirmed in a mouse model of disseminated candidiasis. Confocal laser scanning microscopy revealed that NAM increased cell wall β-glucans exposure and chitin content while decreased mannan level. Furthermore, by screening the C. albicans homozygous deletion mutant library, the C. albicans mutant lacking GIN4, which encodes a septin regulatory protein kinase and is essential for the maintenance of cell wall integrity, was identified to be high sensitive to NAM. These findings suggested that NAM might exhibit antifungal activities through affecting cell wall organization

Lack of Trehalose Accelerates H2O2-Induced Candida albicans Apoptosis through Regulating Ca2+ Signaling Pathway and Caspase Activity

Trehalose is a non-reducing disaccharide and can be accumulated in response to heat or oxidative stresses in Candida albicans. Here we showed that a C. albicans tps1Δ mutant, which is deficient in trehalose synthesis, exhibited increased apoptosis rate upon H2O2 treatment together with an increase of intracellular Ca2+ level and caspase activity. When the intracellular Ca2+ level was stimulated by adding CaCl2 or A23187, both the apoptosis rate and caspase activity were increased. In contrast, the presence of two calcium chelators, EGTA and BAPTA, could attenuate these effects. Moreover, we investigated the role of Ca2+ pathway in C. albicans apoptosis and found that both calcineurin and the calcineurin-dependent transcription factor, Crz1p, mutants showed decreased apoptosis and caspase activity upon H2O2 treatment compared to the wild-type cells. Expression of CaMCA1, the only gene found encoding a C. albicans metacaspase, in calcineurin-deleted or Crz1p-deleted cells restored the cell sensitivity to H2O2. Our results suggest that Ca2+ and its downstream calcineurin/Crz1p/CaMCA1 pathway are involved in H2O2 -induced C. albicans apoptosis. Inhibition of this pathway might be the mechanism for the protective role of trehalose in C. albicans

Evolution of Cooperation Driven by Reputation-Based Migration

How cooperation emerges and is stabilized has been a puzzling problem to biologists and sociologists since Darwin. One of the possible answers to this problem lies in the mobility patterns. These mobility patterns in previous works are either random-like or driven by payoff-related properties such as fitness, aspiration, or expectation. Here we address another force which drives us to move from place to place: reputation. To this end, we propose a reputation-based model to explore the effect of migration on cooperation in the contest of the prisoner's dilemma. In this model, individuals earn their reputation scores through previous cooperative behaviors. An individual tends to migrate to a new place if he has a neighborhood of low reputation. We show that cooperation is promoted for relatively large population density and not very large temptation to defect. A higher mobility sensitivity to reputation is always better for cooperation. A longer reputation memory favors cooperation, provided that the corresponding mobility sensitivity to reputation is strong enough. The microscopic perception of the effect of this mechanism is also given. Our results may shed some light on the role played by migration in the emergence and persistence of cooperation

Monetary Policy’s Regulation and Control of Housing Prices under the Novel Coronavirus Pneumonia Epidemic

In recent years, the downward pressure and uncertain factors of my country’s economic development have gradually increased, especially due to the greater impact of the novel coronavirus pneumonia epidemic in early 2020, it is necessary to adjust the monetary policy to make the economy operate stably. Monetary policy is the main means of controlling housing prices, so this article uses the sample data of my country from January 2011 to September 2020, and uses the time-varying parameter vector autoregressive (TVP-SV-VAR) model under the background of economic policy uncertainty (EPU) for the first time to analyze the price-based and quantitative monetary policies are very necessary to regulate and control housing prices. The study found that the increase in economic policy uncertainty will weaken the regulatory role of quantitative monetary policy but will strengthen the regulatory role of price-based monetary policy; the current economic policy uncertainty has increased, especially since the outbreak of the novel coronavirus pneumonia, the quantitative monetary policy is unstable, and the price-based monetary policy is the best choice for controlling housing prices

Complete convergence and complete moment convergence for negatively associated sequences of random variables

Abstract In this paper, we study the complete convergence and complete moment convergence for negatively associated sequences of random variables with E X = 0 $\mathbb{E}X=0$ , E exp ( ln α | X | ) < ∞ $\mathbb{E}\exp(\ln^{\alpha}|X| )<\infty$ , α > 1 $\alpha>1$ . As a result, we extend some complete convergence and complete moment convergence theorems for independent random variables to the case of negatively associated random variables without necessarily imposing any extra conditions. Our results generalize corresponding results obtained by Gut and Stadtmüller (Stat. Probab. Lett. 81:1486-1492, 2011) and Qiu and Chen (Stat. Probab. Lett. 91:76-82, 2014)

The almost sure local central limit theorem for products of partial sums under negative association

Abstract Let {Xn,n≥1} $\{X_{n}, n\geq1\}$ be a strictly stationary negatively associated sequence of positive random variables with EX1=μ>0 $\mathrm{E}X_{1}=\mu>0$ and Var(X1)=σ20 $\sigma_{1}^{2}=1+\frac{1}{\sigma^{2}}\sum_{j=2}^{\infty}\operatorname{Cov}(X_{1},X_{j})>0$

The Almost Sure Local Central Limit Theorem for the Negatively Associated Sequences

In this paper, the almost sure central limit theorem is established for sequences of negatively associated random variables: limn→∞(1/logn)∑k=1n(I(ak≤Sk<bk)/k)P(ak≤Sk<bk)=1, almost surely. This is the local almost sure central limit theorem for negatively associated sequences similar to results by Csáki et al. (1993). The results extend those on almost sure local central limit theorems from the i.i.d. case to the stationary negatively associated sequences

Some Strong Limit Theorems for Weighted Product Sums of <inline-formula> <graphic file="1029-242X-2009-174768-i1.gif"/></inline-formula>-Mixing Sequences of Random Variables

<p/> <p>We study almost sure convergence for <inline-formula> <graphic file="1029-242X-2009-174768-i2.gif"/></inline-formula>-mixing sequences of random variables. Many of the previous results are our special cases. For example, the authors extend and improve the corresponding results of Chen et al. (1996) and Wu and Jiang (2008). We extend the classical Jamison convergence theorem and the Marcinkiewicz strong law of large numbers for independent sequences of random variables to <inline-formula> <graphic file="1029-242X-2009-174768-i3.gif"/></inline-formula>-mixing sequences of random variables without necessarily adding any extra conditions.</p