Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues

On generators of transition semigroups associated to semilinear stochastic partial differential equations

Let $\mathcal{X}$ be a real separable Hilbert space. Let $Q$ be a linear, self-adjoint, positive, trace class operator on $\mathcal{X}$, let $F:\mathcal{X}\rightarrow\mathcal{X}$ be a (smooth enough) function and let $\{W(t)\}_{t\geq 0}$ be a $\mathcal{X}$-valued cylindrical Wiener process. For $\alpha\in [0,1/2]$ we consider the operator $A:=-(1/2)Q^{2\alpha-1}:Q^{1-2\alpha}(\mathcal{X})\subseteq\mathcal{X}\rightarrow\mathcal{X}$. We are interested in the mild solution $X(t,x)$ of the semilinear stochastic partial differential equation \begin{gather} \left\{\begin{array}{ll} dX(t,x)=\big(AX(t,x)+F(X(t,x))\big)dt+ Q^{\alpha}dW(t), & t>0;\\ X(0,x)=x\in \mathcal{X}, \end{array} \right. \end{gather} and in its associated transition semigroup \begin{align} P(t)\varphi(x):=E[\varphi(X(t,x))], \qquad \varphi\in B_b(\mathcal{X}),\ t\geq 0,\ x\in \mathcal{X}; \end{align} where $B_b(\mathcal{X})$ is the space of the real-valued, bounded and Borel measurable functions on $\mathcal{X}$. In this paper we study the behavior of the semigroup $P(t)$ in the space $L^2(\mathcal{X},\nu)$, where $\nu$ is the unique invariant probability measure of \eqref{Tropical}, when $F$ is dissipative and has polynomial growth. Then we prove the logarithmic Sobolev and the Poincar\'e inequalities and we study the maximal Sobolev regularity for the stationary equation $$\lambda u-N_2 u=f,\qquad \lambda>0,\ f\in L^2(\mathcal{X},\nu);$$ where $N_2$ is the infinitesimal generator of $P(t)$ in $L^2(\mathcal{X},\nu)$

Effects of the combination between selected phytochemicals and the carriers silica and Tween 80 on dry matter and neutral detergent fibre digestibility of common feeds

The overall objective of the current study was to evaluate the effects of 2 carriers (Silica, SIL, and Tween 80, T80) and their interaction with 8 phytochemicals (PCs), on in vitro dry matter and neutral detergent fibre digestibility (DMD, NDFD) of 3 substrates commonly used as feed for dairy cattle (soybean meal, maize meal and total mixed ration –TMR). A total of eight PCs were tested: 4 essential oils (EO) - cinnamon oil (CIN), clove oil (CLO), thyme oil (THY) and oregano oil (ORE) - and 4 essential oil active compounds (EOAC) - cinnamaldehyde (CIN-AC), eugenol (EUG), thymol (THY-AC) and carvacrol (CAR). A positive control with carrier and no PCs was tested for each substrate (CRR). Each PC was tested at 0.5 mg L−1 of medium on DMD and NDFD in an in vitro batch fermentation system. The incubation was performed twice at the intervals of 4 (DMD4, NDFD4) and 24 (DMD24, NDFD24) h. The PCs effect was significant on maize meal and soybean meal DMD24. The carrier’s effect was significant on soybean meal DMD24, indicating a depressive effect of T80 on soybean meal. The PC-carrier interactions were significant on both DMD and NDFD of the tested substrates, except for maize meal and soybean meal DMD24. The PCs-SIL combinations generally increased digestibility while the combination with T80 exerted positive effect only on maize DMD4. The PC-carrier combinations variably affect digestibility of different substrates and these interactions should be considered both for their scientific and commercial implications.HIGHLIGHTS PC-Carrier interactions affect in vitro digestibility. In general, the PC-SIL combinations increase digestibility while those with Tween 80 exert depressing effect. The PC-Carrier effect is variable depending on the degraded substrate