Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and ...lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants.
The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model.
Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway.
Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.
This article presents an adaptive fuzzy fixed time time-varying formation control (TVFC) method for uncertain heterogeneous nonlinear multiagent systems (HNMASs) with full state constraints. ...Meanwhile, both partial loss of effectiveness and bias fault are considered in HNMASs. The fuzzy logic systems are selected as an effective tool to approximate uncertain nonlinear functions. The original constrained states of the systems will be converted to unconstrained states by the nonlinear transformed function. Compared with previous papers, it is the first time to handle the TVFC problem of HNMASs with full state constraints. In addition, formation control based on an adaptive fuzzy fixed time strategy not only ensures fast convergence of the system, but also the convergence time doesn't depend on any initial conditions. The stability of HNMAs is proven by the fixed time stability theory. Finally, a simulation is given to testify the effectiveness of the control method.
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. ...Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
Macromolecular crystallization has many implications in biological and materials science. Similar to the crystallization of other molecules, macromolecular crystallization conventionally considers a ...critical nucleus, followed by crystallographic packing of macromolecules to drive further crystal growth. Herein, we discover a distinctive macromolecular crystallization pathway by developing the concept of a macromolecular mesocrystal. This nonclassical polymer crystallization occurs through the mesoscale self‐assembly of (bio)macromolecular nanocrystals. The new concept for macromolecular crystallization presented herein is fundamental and relevant to many fields, including materials science, chemistry, biomimetics, nanoscience, and structural biology.
Designable macromolecular crystals! The concept of a macromolecular mesocrystal is developed and applied to the discovery of a distinctive macromolecular crystallization pathway. By using the programmed mesoscale assembly and fusion of core–shell architectures, flexible crystalline macromolecular materials with complex forms and hierarchies can be facilely manipulated.
Advances in material design and applications are highly dependent on the development of particle surface engineering strategies. However, few universal methods can functionalize particles of ...different compositions, sizes, shapes, and structures. The amyloid‐like lysozyme assembly‐mediated surface functionalization of inorganic, polymeric or metal micro/nanoparticles in a unique amyloid‐like phase‐transition buffer containing lysozyme are described. The rapid formation of a robust nanoscale phase‐transitioned lysozyme (PTL) coating on the particle surfaces presents strong interfacial binding to resist mechanical and chemical peeling under harsh conditions and versatile surface functional groups to support various sequential surface chemical derivatizations, such as radical living graft polymerization, the electroless deposition of metals, biomineralization, and the facile synthesis of Janus particles and metal/protein capsules. Being distinct from other methods, the preparation of this pure protein coating under biocompatible conditions (e.g., neutral pH and nontoxic reagents) provides a reliable opportunity to directly modify living cell surfaces without affecting their biological activity. The PTL coating arms yeasts with a functional shell to protect their adhered body against foreign enzymatic digestion. The PTL coating further supports the surface immobilization of living yeasts for heterogeneous microbial reactions and the sequential surface chemical derivatization of the cell surfaces, e.g., radical living graft polymerization.
Few universal methods can functionalize particles of different compositions, sizes, shapes, and structures. This study describes the amyloid‐like protein‐assembly‐mediated surface modification and functionalization of particles and living colloids with different compositions, sizes, shapes, and structures. The establishment of this new surface engineering technique for particles and living cells can lead to a diverse array of tools for chemistry and materials.
RAB GTPases (RABs) control intracellular membrane trafficking with high precision. In the present study, we carried out a short hairpin RNA (shRNA) screen focused on a library of 62 RABs during ...infection with porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), a member of the family Arteriviridae. We found that 13 RABs negatively affect the yield of PRRSV-2 progeny virus, whereas 29 RABs have a positive impact on the yield of PRRSV-2 progeny virus. Further analysis revealed that PRRSV-2 infection transcriptionally regulated RAB18 through RIG-I/MAVS-mediated canonical NF-κB activation. Disrupting RAB18 expression led to the accumulation of lipid droplets (LDs), impaired LDs catabolism, and flawed viral replication and assembly. We also discovered that PRRSV-2 co-opts chaperone-mediated autophagy (CMA) for lipolysis via RAB18, as indicated by the enhanced associations between RAB18 and perlipin 2 (PLIN2), CMA-specific lysosomal associated membrane protein 2A (LAMP2A), and heat shock protein family A (Hsp70) member 8 (HSPA8/HSC70) during PRRSV-2 infection. Knockdown of HSPA8 and LAMP2A impacted on the yield of PRRSV-2 progeny virus, implying that the virus utilizes RAB18 to promote CMA-mediated lipolysis. Importantly, we determined that the C-terminal domain (CTD) of HSPA8 could bind to the switch II domain of RAB18, and the CTD of PLIN2 was capable of associating with HSPA8, suggesting that HSPA8 facilitates the interaction between RAB18 and PLIN2 in the CMA process. In summary, our findings elucidate how PRRSV-2 hijacks CMA-mediated lipid metabolism through innate immune activation to enhance the yield of progeny virus, offering novel insights for the development of anti-PRRSV-2 treatments.
The HIV epidemic is rapidly growing among men who have sex with men (MSM) in China, yet HIV testing remains suboptimal. We aimed to determine the impact of HIV self-testing (HIVST) interventions on ...frequency of HIV testing among Chinese MSM and their sexual partners.
This randomized controlled trial was conducted in 4 cities in Hunan Province, China. Sexually active and HIV-negative MSM were recruited from communities and randomly assigned (1:1) to intervention or control arms. Participants in the control arm had access to site-based HIV testing (SBHT); those in the intervention arm were provided with 2 free finger-prick-based HIVST kits at enrollment and could receive 2 to 4 kits delivered through express mail every 3 months for 1 year in addition to SBHT. They were encouraged to distribute HIVST kits to their sexual partners. The primary outcome was the number of HIV tests taken by MSM participants, and the secondary outcome was the number of HIV tests taken by their sexual partners during 12 months of follow-up. The effect size for the primary and secondary outcomes was evaluated as the standardized mean difference (SMD) in testing frequency between intervention and control arms. Between April 14, 2018, and June 30, 2018, 230 MSM were recruited. Mean age was 29 years; 77% attended college; 75% were single. The analysis population who completed at least one follow-up questionnaire included 110 (93%, 110/118) in the intervention and 106 (95%, 106/112) in the control arm. The average frequency of HIV tests per participant in the intervention arm (3.75) was higher than that in the control arm (1.80; SMD 1.26; 95% CI 0.97-1.55; P < 0.001). This difference was mainly due to the difference in HIVST between the 2 arms (intervention 2.18 versus control 0.41; SMD 1.30; 95% CI 1.01-1.59; P < 0.001), whereas the average frequency of SBHT was comparable (1.57 versus 1.40, SMD 0.14; 95% CI -0.13 to 0.40; P = 0.519). The average frequency of HIV tests among sexual partners of each participant was higher in intervention than control arm (2.65 versus 1.31; SMD 0.64; 95% CI 0.36-0.92; P < 0.001), and this difference was also due to the difference in HIVST between the 2 arms (intervention 1.41 versus control 0.36; SMD 0.75; 95% CI 0.47-1.04; P < 0.001) but not SBHT (1.24 versus 0.96; SMD 0.23; 95% CI -0.05 to 0.50; P = 0.055). Zero-inflated Poisson regression analyses showed that the likelihood of taking HIV testing among intervention participants were 2.1 times greater than that of control participants (adjusted rate ratio RR 2.10; 95% CI 1.75-2.53, P < 0.001), and their sexual partners were 1.55 times more likely to take HIV tests in the intervention arm compared with the control arm (1.55, 1.23-1.95, P < 0.001). During the study period, 3 participants in the intervention arm and none in the control arm tested HIV positive, and 8 sexual partners of intervention arm participants also tested positive. No other adverse events were reported. Limitations in this study included the data on number of SBHT were solely based on self-report by the participants, but self-reported number of HIVST in the intervention arm was validated; the number of partner HIV testing was indirectly reported by participants because of difficulties in accessing each of their partners.
In this study, we found that providing free HIVST kits significantly increased testing frequency among Chinese MSM and effectively enlarged HIV testing coverage by enhancing partner HIV testing through distribution of kits within their sexual networks.
Chinese Clinical Trial Registry ChiCTR1800015584.
•Binding interaction of four selected inhibitors and mPPO was investigated.•A static quenching mechanism was involved in the interaction process in inhibitors.•Six amino acid residues were the ...preferred binding sites within the active center.•Four selected inhibitors bound to mPPO mainly by hydrogen bond and ion contact.
We investigated the inhibitory effect and binding mechanism of four selected compounds (ascorbic acid, l-cysteine, glutathione, and citric acid) on membrane-bound polyphenol oxidases (mPPO) using spectroscopic and molecular docking techniques. Kinetic analysis demonstrated that these inhibitors reversibly inhibited the mPPO activity. Fluorescence spectroscopy revealed that the intrinsic fluorescence intensity of mPPO was quenched by inhibitors with a single class of the inhibition site on mPPO. Amino acid residues His 180, His 201, His 366, Cys 184, Glu 328, and Asn 333 were the important binding sites in the active center. These sites were identified using molecular docking techniques. Our findings suggested that the inhibitors were allosterically bound to the active center of mPPO through hydrogen bonds and ion contacts. This study provides new insights into the active site residues responsible for catalyzing mPPO and provides applicable information about the design of mPPO inhibitors.
Summary
This article studies the fixed‐time time‐invariant formation control problem for a class of uncertain nonlinear heterogeneous multi‐agent systems (HMASs) with actuator faults and partial ...unknown control directions. Throughout the formation process, the possibility of actuator faults in systems and unknown control directions between individual agents are taken into account. Lipschitz conditions are introduced to identify the continuous uncertain nonlinear functions. To estimate the agents' local immeasurable states in HMASs, a distributed fixed‐time observer is proposed, which can ensure that the states of follower agents are observed in fixed time. In addition, a distributed formation fault‐tolerant control scheme will handle actuator faults. By designing a Nussbaum function, the problem of partial unknown control directions for HMASs can be solved in fixed time. Based on the fixed time stability theory, it is proved that the closed‐loop stability and the tracking performance can be guaranteed in fixed time, that is, the achieved time is independent of any initial states. In the end, a simulation example is given to testify the effectiveness of the proposed control method.
Depression is common among people living with HIV (PLHIV). Studies on the relationship between depression and use of antiretroviral therapy (ART) are inconclusive. A meta-analysis was conducted to ...summarize the relationship between depression and ART use among PLHIV. Ten electronic databases, conference abstracts, and dissertations were searched. A random effects meta-analysis was performed to pool the odds ratio estimates from eligible studies. Subgroup analyses and meta-regression were conducted for moderator analysis. Sensitivity analysis was performed to find influential studies. A funnel plot, the Egger test, and the trim and fill analysis were used to detect publication bias. The pooled sample size was 7375 PLHIV from nine eligible studies. The pooled prevalence of depression was 41% (95% confidence interval CI 29–53%). The pooled ART use rate was 52% (95% CI 37–67%). PLHIV with depression were 14% less likely (pooled odds ratio OR = 0.86; 95% CI 0.71–1.05) to use ART than those without depression. Subgroup analyses showed that depression was significantly associated with no ART use (pooled OR 0.84; 95% CI 0.71–0.99) among studies with a prospective study design (11 estimates from nine studies). Moderator analyses did not show any statistically significant effects. The publication bias analyses showed small study effects may not exist. Depression was associated with non-use of ART among PLHIV. Studies are needed to explore this association in other countries with varied populations, as most published studies have been conducted in the United States.
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