Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.

The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.

An archaeal transcription factor EnfR with a novel 'eighth note' fold controls hydrogen production of a hyperthermophilic archaeon Thermococcus onnurineus NA1.

Thermococcus onnurineus NA1, a hyperthermophilic carboxydotrophic archaeon, produces H2 through CO oxidation catalyzed by proteins encoded in a carbon monoxide dehydrogenase (CODH) gene cluster. TON_1525 with a DNA-binding helix-turn-helix (HTH) motif is a putative repressor regulating the transcriptional expression of the codh gene cluster. The T55I mutation in TON_1525 led to enhanced H2 production accompanied by the increased expression of genes in the codh cluster. Here, TON_1525 was demonstrated to be a dimer. Monomeric TON_1525 adopts a novel 'eighth note' symbol-like fold (referred to as 'eighth note' fold regulator, EnfR), and the dimerization mode of EnfR is unique in that it has no resemblance to structures in the Protein Data Bank. According to footprinting and gel shift assays, dimeric EnfR binds to a 36-bp pseudo-palindromic inverted repeat in the promoter region of the codh gene cluster, which is supported by an in silico EnfR/DNA complex model and mutational studies revealing the implication of N-terminal loops as well as HTH motifs in DNA recognition. The DNA-binding affinity of the T55I mutant was lowered by ∼15-fold, for which the conformational change of N-terminal loops is responsible. In addition, transcriptome analysis suggested that EnfR could regulate diverse metabolic processes besides H2 production.

Associations between perceived and actual risk of HIV infection and HIV prevention services uptake among men who have sex with men in Shandong province, China: a cross-sectional study.

BACKGROUND: Associations between perceived and actual risk of HIV infection and HIV prevention services uptake are inconclusive. This study aimed to evaluate the discrepancy between the perceived and actual HIV risk, and quantify the associations between perceived and actual risk of HIV infection and three HIV prevention services utilization among men who have sex with men (MSM) in Shandong province, China. METHODS: A cross-sectional study was conducted in Shandong province in June 2021. Participants were eligible if they were born biologically male, aged 18 years or older, had negative or unknown HIV status, and had sex with men in the past year. Participants were recruited online. The discrepancy between their perceived and actual risk of HIV infection was evaluated by calculating the Kappa value. Bayesian model averaging was used to assess the associations between perceived and actual risk of HIV infection and HIV prevention services uptake. RESULTS: A total of 1136 MSM were recruited, most of them were 30 years old or younger (59.9%), single (79.5%), with at least college education level (74.7%). Most participants (97.4%) perceived that they had low risk of HIV infection, and 14.1% were assessed with high actual risk. The discrepancy between their perceived and actual risk of HIV infection was evaluated with a Kappa value of 0.076 (P < 0.001). HIV testing uptake had a weak association with perceived high HIV prevalence among social networks (aOR = 1.156, post probability = 0.547). The perceived high HIV prevalence among national MSM was positive related to willingness to use PrEP (aOR = 1.903, post probability = 0.943) and PEP (aOR = 1.737, post probability = 0.829). Perceived personal risk (aOR = 4.486, post probability = 0.994) and perceived HIV prevalence among social networks (aOR = 1.280, post probability = 0.572) were related to history of using PrEP. Perceived personal risk (aOR = 3.144, post probability = 0.952), actual risk (aOR = 1.890, post probability = 0.950), and perceived risk among social networks (aOR = 1.502, post probability = 0.786) were related to history of using PEP. CONCLUSIONS: There is discordance between perceived and actual personal risk of HIV infection among MSM in China. HIV risk assessment and education on HIV prevalence among MSM should be strengthened to assist high-risk populations aware their risk accurately and hence access HIV prevention services proactively.

HIV Status Disclosure and Associated Characteristics Among HIV-Positive MSM Receiving Antiretroviral Therapy in Jinan, China.

Disclosure of HIV status offers potential benefits to individuals and is also good for public health. Limited studies have been conducted to gain insight into the current situation and associated factors of HIV disclosure among HIV-positive Chinese men who have sex with men (MSM) in the era of "treat all." We carried out a cross-sectional study among MSM receiving antiretroviral therapy from October 2020 to January 2021 at a hospital in Jinan, China. We used univariate and multivariable logistic regression to examine the factors associated with general disclosure and disclosure to family, friends, and sexual partners. Of the 585 participants recruited, 62.2% reported HIV disclosure, among which 25.3% had disclosed their status to family members, 25.3% had disclosed it to friends, and 28.4% had disclosed it to partners. The findings suggest that HIV disclosure is more likely to occur among individuals who are younger, married/cohabiting, and who self-identify as homosexual/bisexual. Participants with higher education levels or personal monthly incomes are less likely to disclose their HIV status. Furthermore, related factors of disclosure vary across the types of disclosure targets. Given the positive outcomes of disclosure, interventions and implementation research to facilitate it are urgently needed for MSM.

Alcohol consumption and utilization of HIV prevention services among men who have casual sex with women in China.

Men who have casual sex with women (MCSW) have played an important role in HIV new infections in China. Research studies have shown that heavy alcohol consumption can increase the risk of HIV infection. The cross-sectional study was conducted in two cities in China from December 2018 to May 2019 to examine the association between alcohol consumption and utilization of HIV prevention services among MCSW. Convenience sampling was used to recruit participants and 400 MCSW were recruited in this study. There were 238 (59.6%), 213 (53.4%) and 129 (32.4%) participants having utilized HIV prevention services, condom promotion and distribution or HIV counseling and testing (CPD/HCT) services, and peer education services in the past 12 months, respectively. MCSW who were identified as heavy drinkers were less likely to utilize HIV prevention services and CPD/HCT services compared with non-drinkers. For youngsters, those who are in the local household and those who are married/cohabitating, heavy drinkers was less likely to utilize HIV prevention services. This study highlights the significance of intensive education on heavy drinkers of MCSW, particularly for high-risk subgroups. Targeting resources for integrated HIV prevention efforts with alcohol-using MCSW should be considered by public health policymakers.

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer.

Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2 By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.

Digital, Crowdsourced, Multilevel Intervention to Promote HIV Testing Among Men Who Have Sex With Men: Cluster Randomized Controlled Trial.

BACKGROUND: Despite great efforts in HIV prevention worldwide, HIV testing uptake among men who have sex with men (MSM) remains suboptimal. The effectiveness of digital, crowdsourced, multilevel interventions in improving HIV testing is still unclear. OBJECTIVE: The aim of this study was to evaluate the effect of a digital, crowdsourced, multilevel intervention in improving HIV testing uptake among MSM in China. METHODS: We conducted a 2-arm cluster randomized controlled trial among MSM in 11 cities in Shandong province, China, from August 2019 to April 2020. Participants were men who were HIV seronegative or had unknown serum status, had anal sex with a man in the past 12 months, and had not been tested for HIV in the past 3 months. Participants were recruited through a gay dating app and community-based organizations from preselected cities; these cities were matched into 5 blocks (2 clusters per block) and further randomly assigned (1:1) to receive a digital, crowdsourced, multilevel intervention (intervention arm) or routine intervention (control arm). The digital multilevel intervention was developed through crowdsourced open calls tailored for MSM, consisting of digital intervention images and videos, the strategy of providing HIV self-testing services through digital tools, and peer-moderated discussion within WeChat groups. The primary outcome was self-reported HIV testing uptake in the previous 3 months. An intention-to-treat approach was used to examine the cluster-level effect of the intervention in the 12-month study period using generalized linear mixed models and the individual-level effect using linear mixed models. RESULTS: A total of 935 MSM were enrolled (404 intervention participants and 531 controls); 751 participants (80.3%) completed at least one follow-up survey. Most participants were younger than 30 years (n=601, 64.3%), single (n=681, 72.8%), had a college degree or higher (n=629, 67.3%), and had an HIV testing history (n=785, 84%). Overall, the proportion of testing for HIV in the past 3 months at the 3-, 6-, 9-, and 12-month follow-ups was higher in the intervention arm (139/279, 49.8%; 148/266, 55.6%; 189/263, 71.9%; and 171/266, 64.3%, respectively) than the control arm (183/418, 43.8%; 178/408, 43.6%; 206/403, 51.1%; and 182/397, 48.4%, respectively), with statistically significant differences at the 6-, 9-, and 12-month follow-ups. At the cluster level, the proportion of participants who had tested for HIV increased 11.62% (95% CI 0.74%-22.5%; P=.04) with the intervention. At the individual level, participants in the intervention arm had 69% higher odds for testing for HIV in the past 3 months compared with control participants, but the result was not statistically significant (risk ratio 1.69, 95% CI 0.87-3.27; P=.11). CONCLUSIONS: The intervention effectively improved HIV testing uptake among Chinese MSM. Our findings highlight that digital, crowdsourced, multilevel interventions should be made more widely available for HIV prevention and other public health issues. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900024350; http://www.chictr.org.cn/showproj.aspx?proj=36718. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-04860-8.

Drug users' awareness of and willingness to use HIV non-occupational post-exposure prophylaxis (nPEP) services in China: a mixed methods study.

BACKGROUND: Drug users are regarded as a high-risk population for HIV infection. Non-occupational post-exposure prophylaxis (nPEP) is internationally regarded as an effective biomedical prevention against HIV but still a small-scale pilot project in China at present. The aim of this study was to understand drug users' awareness of and willingness to use nPEP service in China. METHODS: This mixed methods study consisting of a qualitative study and a cross-sectional survey was conducted in two cities of China from 2018 to 2019. The in-depth interviews were audio-taped, transcribed verbatim and analyzed using thematic framework analysis. Univariate and multivariate logistic regressions were used to examine factors associated with drug users' awareness of and willingness to use nPEP. RESULTS: There were 401 and 19 participants included in quantitative and qualitative study respectively. Among participants in quantitative study, 30.2% had heard of nPEP and 56.7% reported willingness to use nPEP in future HIV exposure. In multivariate analyses, nPEP awareness was associated with age, sex, education level, AIDS knowledge score and HIV risk perception. nPEP willingness was associated with AIDS knowledge score, HIV risk perception, alcohol use, monthly income and awareness of nPEP. The qualitative results showed the barriers to nPEP willingness included the fatigue after taking drugs, high cost and side effects of nPEP medication, long nPEP course, and fear of privacy disclosure. CONCLUSION: Drug users had low nPEP awareness and only about half participants reported willingness to use nPEP. It is essential to promote nPEP education campaigns among drug users, especially for elders, women and those with lower education level. Simultaneously, price regulation, side effect management, psychological support and privacy protection need to be managed well when nPEP is routinized.

HIV infection disclosure, treatment self-efficacy and quality of life in HIV-infected MSM receiving antiretroviral therapy.

BACKGROUND: Research on the relationship between disclosure of HIV status to male sexual partners (HIV disclosure) and quality of life (QOL) revealed complex and even contradictory results. The impact of HIV disclosure on various domains of QOL and the mediation effect between them are unclear. The purposes of this study were to explore the impact of HIV disclosure on QOL among men who have sex with men (MSM), and whether HIV treatment self-efficacy mediated these relationships. METHODS: The data came from a baseline survey on the design of a randomized control trial conducted in Shandong, China. A total of 579 MSM patients were included. SPSS 24.0 was used to conduct independent samples t test, one-way analysis of variance and nonparametric tests and the PROCESS macro was used to conduct mediation analysis. RESULTS: Among 579 participants, 16.06% disclosed their HIV infection status to their male sexual partners. The effect of HIV disclosure on QOL was mediated by treatment self-efficacy. Self-efficacy played partial mediating role in social relationships, meaning that HIV disclosure had both direct and indirect effects on this factor. In the overall QOL and domains of physical, psychological, independence, and environment, HIV disclosure had an indirect effect only through self-efficacy and no significant effect on the spirituality domain. CONCLUSIONS: The results emphasize the importance of HIV disclosure and self-efficacy on the QOL of MSM patients and suggest that health care providers should assist MSM patients in deciding whether to disclose their HIV status during daily medical services.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

The Multivalent Polyampholyte Domain of Nst1, a P-Body-Associated Saccharomyces cerevisiae Protein, Provides a Platform for Interacting with P-Body Components.

The condensation of nuclear promyelocytic leukemia bodies, cytoplasmic P-granules, P-bodies (PBs), and stress granules is reversible and dynamic via liquid-liquid phase separation. Although each condensate comprises hundreds of proteins with promiscuous interactions, a few key scaffold proteins are required. Essential scaffold domain sequence elements, such as poly-Q, low-complexity regions, oligomerizing domains, and RNA-binding domains, have been evaluated to understand their roles in biomolecular condensation processes. However, the underlying mechanisms remain unclear. We analyzed Nst1, a PB-associated protein that can intrinsically induce PB component condensations when overexpressed. Various Nst1 domain deletion mutants with unique sequence distributions, including intrinsically disordered regions (IDRs) and aggregation-prone regions, were constructed based on structural predictions. The overexpression of Nst1 deletion mutants lacking the aggregation-prone domain (APD) significantly inhibited self-condensation, implicating APD as an oligomerizing domain promoting self-condensation. Remarkably, cells overexpressing the Nst1 deletion mutant of the polyampholyte domain (PD) in the IDR region (Nst1∆PD) rarely accumulate endogenous enhanced green fluorescent protein (EGFP)-tagged Dcp2. However, Nst1∆PD formed self-condensates, suggesting that Nst1 requires PD to interact with Dcp2, regardless of its self-condensation. In Nst1∆PD-overexpressing cells treated with cycloheximide (CHX), Dcp2, Xrn1, Dhh1, and Edc3 had significantly diminished condensation compared to those in CHX-treated Nst1-overexpressing cells. These observations suggest that the PD of the IDR in Nst1 functions as a hub domain interacting with other PB components.

The N-linked glycosylations of TIGIT Asn32 and Asn101 facilitate PVR/TIGIT interaction.

Although the PVR/TIGIT immune checkpoint axis has been suggested as a promising target for cancer immunotherapy and multiple TIGIT-targeting therapies are undergoing clinical trials, the underlying regulatory mechanisms of PVR/TIGIT interaction remain inconclusive. Here we show that TIGIT N-glycosylations are critical for maintaining the interaction between TIGIT and PVR. TIGIT has two N-glycosylation residues, N32 and N101. N-glycosylation on N101 of TIGIT and, to less extent, on N32, play potent roles in PVR binding. Taken together, these findings suggest that the N-glycosylation sites on TIGIT, especially residue N101, may be potential targets for PVR/TIGIT immune checkpoint blockade.

The mediated effect of HIV risk perception in the relationship between peer education and HIV testing uptake among three key populations in China.

BACKGROUND: Peer education and HIV risk perception are related to HIV testing uptake among key populations. We aimed to examine the association between peer education, HIV risk perception, and HIV testing uptake, as well as to evaluate the mediated effect of HIV risk perception in the relationship between peer education and HIV testing uptake. METHODS: We conducted a cross-sectional survey among 1188 HIV-uninfected or unknown participants from populations of men who have sex with men (MSM), female sex workers (FSWs), and drug users (DUs) in seven cities of China. Partial correlation analysis and regression analysis were employed to examine the associations among peer education, HIV risk perception, and HIV testing uptake. Mediation analysis was conducted to assess whether HIV risk perception mediated the hypothesized association. RESULTS: Receiving peer education was associated with higher odds of HIV testing uptake among MSM, FSWs and DUs. Perceiving risk of HIV infection was associated with higher odds of HIV testing uptake among MSM and DUs. Among MSM, the relationship between peer education and HIV testing uptake was mediated by moderate risk perception of HIV (indirect effect: 0.53, 95% CI 0.07 to 1.21), and by high risk perception of HIV (indirect effect: 0.50, 95% CI 0.01 to 1.17). Among DUs, the relationship between peer education and HIV testing uptake was mediated by moderate risk perception of HIV (indirect effect: 1.80, 95% CI 0.57 to 3.45). CONCLUSIONS: Participants who received peer education tended to perceive their risk of HIV infection, which in turn was associated with increased HIV testing uptake among MSM and DUs. Therefore, in addition to peer education interventions, more report about HIV epidemic and risk assessment should also be scaled up to enhance HIV risk perception among key populations.

Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease.

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 µM), and alphacoronavirus PEDV (IC50 value of 7.51 µM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.

Ca2+ Regulates ERp57-Calnexin Complex Formation.

ERp57, a member of the protein disulfide isomerase family, is a ubiquitous disulfide catalyst that functions in the oxidative folding of various clients in the mammalian endoplasmic reticulum (ER). In concert with ER lectin-like chaperones calnexin and calreticulin (CNX/CRT), ERp57 functions in virtually all folding stages from co-translation to post-translation, and thus plays a critical role in maintaining protein homeostasis, with direct implication for pathology. Here, we present mechanisms by which Ca2+ regulates the formation of the ERp57-calnexin complex. Biochemical and isothermal titration calorimetry analyses revealed that ERp57 strongly interacts with CNX via a non-covalent bond in the absence of Ca2+. The ERp57-CNX complex not only promoted the oxidative folding of human leukocyte antigen heavy chains, but also inhibited client aggregation. These results suggest that this complex performs both enzymatic and chaperoning functions under abnormal physiological conditions, such as Ca2+ depletion, to effectively guide proper oxidative protein folding. The findings shed light on the molecular mechanisms underpinning crosstalk between the chaperone network and Ca2+.

Discovery and evaluation of Atopaxar hydrobromide, a novel JAK1 and JAK2 inhibitor, selectively induces apoptosis of cancer cells with constitutively activated STAT3.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a vital role in immunity, cell division, cell death and tumor formation. Disrupted JAK-STAT signaling may lead to various diseases, especially cancer and immune disorders. Because of its importance, this signaling pathway has received significant attention from the pharmaceutical and biotechnology industries as a therapeutic target for drug design. However, few JAK or STATs inhibitors have been developed for cancer treatment. We used an in vitro STAT3 luciferase reporter assay to find novel inhibitors that could effectively block the JAK-STAT pathway. In our study, we screened 16,081 drug-like chemicals and found that atopaxar hydrobromide (AHB) is a specific inhibitor of JAK-STAT3 signaling. Our results suggest that AHB not only blocks constitutively activated and cytokine-induced STAT3 phosphorylation but also inhibits JAK1 and JAK2 phosphorylation. Moreover, AHB induces G1 phase cell cycle arrest, which stops cancer cell growth and induces apoptosis. AHB also inhibited tumor cell growth in vivo. In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug.

Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling.

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.

Characterizing the structural and thermodynamic properties of Aß42 and Aß40.

The self-assembly of amyloid-beta (Aß) proteins in aqueous extracellular environments is implicated in Alzheimer's disease. Among several alloforms of Aß proteins differing in sequence length, the 42- and 40-residue forms (Aß42 and Aß40) are the most abundant ones in the human body. Although the only difference is the additional I41A42 residues in the C-terminus, Aß42 exhibits more aggregation tendency and stronger neurotoxicity than Aß40. Here, we investigate the molecular factors that confer more aggregation potential to Aß42 than to Aß40 based on molecular dynamics simulations combined with solvation thermodynamic analyses. It is observed that the most salient structural feature of Aß42 relative to Aß40 is the more enhanced ß-sheet forming tendency, in particular in the C-terminal region. While such a structural characteristic of Aß42 will certainly serve to facilitate the formation of aggregate species rich in ß-sheet structure, we also detect its interesting thermodynamic consequence. Indeed, we find from the decomposition analysis that the C-terminal region substantially increases the solvation free energy (i.e., overall "hydrophobicity") of Aß42, which is caused by the dehydration of the backbone moieties showing the enhanced tendency of forming the ß-structure. Together with the two additional hydrophobic residues (I41A42), this leads to the higher solvation free energy of Aß42, implying the larger water-mediated attraction toward the self-assembly. Thus, our computational results provide structural and thermodynamic grounds on why Aß42 has more aggregation propensity than Aß40 in aqueous environments.

Pulmonary Vasodilator Therapy in Shock-associated Cardiac Arrest.

RATIONALE: Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed. OBJECTIVES: To determine if the addition of inhaled nitric oxide (iNO) to hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) would improve short-term survival from cardiac arrest associated with shock and systemic inflammation. METHODS: In 3-month-old swine (n = 21), LPS was intravenously infused, inducing systemic hypotension. Ventricular fibrillation was induced, and animals were randomized to blinded treatment with either: 1) HD-CPR with iNO, or 2) HD-CPR without iNO. During HD-CPR, chest compression depth was titrated to peak aortic compression pressure of 100 mm Hg, and vasopressor administration was titrated to coronary perfusion pressure greater than or equal to 20 mm Hg. Defibrillation attempts began after 10 minutes of resuscitation. The primary outcome was 45-minute survival. MEASUREMENTS AND MAIN RESULTS: The iNO group had higher rates of 45-minute survival (10 of 10 vs. 3 of 11; P = 0.001). During cardiopulmonary resuscitation, the iNO group had lower pulmonary artery relaxation pressure (mean ± SEM, 10.9 ± 2.4 vs. 18.4 ± 2.4 mm Hg; P = 0.03), higher coronary perfusion pressure (21.1 ± 1.5 vs. 16.9 ± 1.0 mm Hg; P = 0.005), and higher aortic relaxation pressure (36.6 ± 1.6 vs. 30.4 ± 1.1 mm Hg; P < 0.001) despite shallower chest compressions (5.88 ± 0.25 vs. 6.46 ± 0.40 cm; P = 0.02) and fewer vasopressor doses in the first 10 minutes (median, 4 [interquartile range, 3-4] vs. 5 [interquartile range, 5-6], P = 0.03). CONCLUSIONS: The addition of iNO to HD-CPR in LPS-induced shock-associated cardiac arrest improved short-term survival and intraarrest hemodynamics.