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Background: Parents of children with hematological cancers such as leukemia and lymphoma need to cope with stress related to their child's diagnosis. The Coping Self-Efficacy Scale is a widely used and validated tool to measure an individual's confidence in dealing with stressful situations. Appropriate translation and validation are needed to produce a localized language version suitable for Malaysian contexts., Objective: The study aimed to examine the linguistic and construct validity of the Malay version of the Coping Self-Efficacy Scale (CSES-My) among parents of children with hematological cancer., Methods: The CSES-My was created through a sequential series of steps, starting with the translation of the original English version, followed by cultural adaptation, and then cognitive interviewing. The 26-item CSES-My was self-administered in a sample of parents of children with leukemia and lymphoma from October 2021 until February 2022. They were recruited via online or face-to-face methods. Exploratory factor analysis was performed to examine the construct validity of the CSES-My., Results: A total of 165 complete responses were analyzed. The scale has two factors, including Personal Coping and Social Coping, accounting for 58.3% of the variance. Personal Coping (19 items, Cronbach's alpha = 0.958) represented the respondents' self-efficacy for independently executing coping strategies, whether through solving problems or changing the way they think about the situation. Social Coping (6 items, Cronbach's alpha = 0.867) represented their confidence in executing coping strategies, which involved using social resources such as seeking external support, distraction, and avoiding loneliness., Conclusions: The CSES-My had reliable and valid psychometric properties, providing evidence for its utility in evaluating coping self-efficacy among parents of children with leukemia or lymphoma in Malaysia. The CSES-My is a valuable tool for nurses and other healthcare professionals investigating coping self-efficacy in Malay-speaking populations, and it may also aid in the development of future coping interventions., Competing Interests: CET was a PhD student under the supervision of KAT and SMS during this study. The authors declare no financial competing interests in the preparation of this manuscript. The funder was not involved in the design or conduct of the study., (© The Author(s) 2024.)

Apicomplexan parasites discharge specialized organelles called rhoptries upon host cell contact to mediate invasion. The events that drive rhoptry discharge are poorly understood, yet essential to sustain the apicomplexan parasitic life cycle. Rhoptry discharge appears to depend on proteins secreted from another set of organelles called micronemes, which vary in function from allowing host cell binding to facilitation of gliding motility. Here we examine the function of the microneme protein CLAMP, which we previously found to be necessary for Toxoplasma gondii host cell invasion, and demonstrate its essential role in rhoptry discharge. CLAMP forms a distinct complex with two other microneme proteins, the invasion-associated SPATR, and a previously uncharacterized protein we name CLAMP-linked invasion protein (CLIP). CLAMP deficiency does not impact parasite adhesion or microneme protein secretion; however, knockdown of any member of the CLAMP complex affects rhoptry discharge. Phylogenetic analysis suggests orthologs of the essential complex components, CLAMP and CLIP, are ubiquitous across apicomplexans. SPATR appears to act as an accessory factor in Toxoplasma, but despite incomplete conservation is also essential for invasion during Plasmodium falciparum blood stages. Together, our results reveal a new protein complex that mediates rhoptry discharge following host-cell contact., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: With the increasing prevalence of obesity in youth, behavioural interventions to alter its modifiable risk factors such as physical activity can support the management of this epidemic. Digital behaviour changes interventions (DBCI) such as mobile applications, websites and wearables have the potential to reach many adolescents to promote physical activity as its use may be more accessible, effective and engaging compared to traditional face-to-face approaches. However, there is insufficient evidence on their use at promoting physical activity amongst overweight and obese adolescents. This review aims to assess the effectiveness of DBCIs aiming to increase physical activity in overweight and obese adolescents (aged 10-19 years) and the behaviour change techniques used in these interventions., Methods: Electronic databases (MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane and Scopus) will be searched for English language studies from January 2000 to December 2022 using appropriate search terms relating to digital interventions, physical activity, adolescents and obesity. Experimental studies (either randomised or non-randomised controlled trials) assessing effects of DBCIs on physical activity behaviour, objectively or subjectively measured, in overweight and obese (body mass index [BMI] ≥ 85th percentile for age) adolescents will be eligible for inclusion. Intervention characteristics will be coded using the Template for Intervention Description and Replication (TIDieR) checklist and the BCT taxonomy v1. Risk of bias and the overall quality of the included studies will be assessed using Cochrane's Collaboration's tool and GRADE approach respectively. If the data allows, meta-analyses using random effect models will be conducted to assess the effects of DBCIs on physical activity., Discussion: The proposed systematic review will summarise the effectiveness of digital behaviour change interventions aiming to increase physical activity in overweight and obese adolescents, as well as adding new information on the behaviour change techniques used in these interventions. The findings of this review will facilitate stakeholders with a current, rigorous and reliable research base to support the development and implementation of effective health promotion interventions for this population., Systematic Review Registration: PROSPERO CRD42021270008., (© 2022. The Author(s).)

Despite the high prevalence of psychological distress in primary care, only a limited number of individuals can benefit from early and evidenced-based psychological approach. Barriers to help-seeking attributable to stigma, lack of proper care pathway to evidence-based psychological interventions, and a high volume of primary care attendees are among the factors that contribute to the inadequate psychological treatments. This study examined the implementation of a change process using a brief cognitive behavioral therapy (b-CBT) workshop as a potential approach in managing psychological distress among 73 primary care self-referrals using purposive sampling. One-way repeated-measures multivariate analysis of variance (ANOVA) was used to analyze changes in psychological distress within a non-randomized quasi-experimental study. Results revealed significant differences in psychological distress using Depression, Anxiety, and Stress Scale-21 items at three time points (pre-intervention, post-intervention, and 1-month follow-up). Implementation of the b-CBT workshop showed positive changes for psychological distress, suggesting the possibility of integrating brief, non-stigmatized, and evidence-based psychological approach at the primary care level. However, the self-referral characteristics of the attendees remain unknown. Factors such as potential feasibility, participant's usability and satisfaction, and implementation of b-CBT workshop to improve psychological distress are discussed in this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sam, Ismail, Tan, Sidik and Osman.)

Background: The awareness and practice of pelvic floor muscle exercise (PFME) in the prevention and reduction of the rate of urinary incontinence among pregnant women was considerably poor, despite the increased prevalence of urinary incontinence during pregnancy across Malaysia. There healthcare providers do not give adequate attention to the potential impact of PFME on urinary incontinence and there is limited local intervention addressed urinary incontinence during pregnancy. The objective of this study was to determine the effectiveness of a newly developed PFME intervention in terms of knowledge, attitude, practice, self-efficacy, and urinary symptoms., Methods: A single-blinded, two-armed, randomized control trial was included pregnant women from 18 to 20 weeks of gestation and was conducted at the Maternity Hospital of Kuala Lumpur. The intervention group received PFME in addition to the usual perinatal care. The data were collected using validated questionnaires at 4 time points: baseline, post-intervention in the early third trimester, late third trimester, and early postnatal period. The intervention effects were analyzed using a generalized estimating equation., Results: The primary analysis included pregnant women who had at least one follow-up; 122 women (71.8%) in the intervention group had significant improvement in knowledge, attitude, practice, and self-efficacy, as well as in the severity of urinary incontinence over time. However, improvement was not observed in self-reported urinary incontinence., Conclusion: PFME can be considered an effective initial intervention to provide information about urinary incontinence prevention to pregnant women.

Objective: Informational support is an important pillar of psychosocial care for parents of children with cancer. Understanding the information needs of these parents may improve the provision of family-centered informational support. This paper aims to explore the information needs of Malaysian parents whose children have cancer., Methods: This qualitative study was conducted among 14 parents of children with cancer and 8 healthcare providers. The parents were recruited from two urban pediatric oncology centers in Malaysia. Healthcare providers were recruited from these centers, as well as from community-based palliative care providers. In-depth interviews were conducted based on semi-structured topic guides, audio-recorded, and transcribed for thematic analysis using elements of the grounded theory approach., Results: Analysis revealed three themes of information needs, which were: "interaction with the healthcare system," "care for the child at home" and "psychosocial support for parents". Information needs on parents' interaction with the healthcare system consisted of disease and treatment-related information, as well as health system navigation. Information needs on care for the child at home were represented by their caregiving for basic activities of daily living, medical caregiving, and psychosocial caregiving. Psychosocial support for parents included information on practical support and self-care. There were differences in priorities for information needs between parents and healthcare providers., Conclusions: Meeting the information needs of parents is an important part of psychosocial care in pediatric cancer care. Informational support may empower parents in caregiving for their child. The development of suitable information resources will be invaluable for healthcare providers in supporting parents' needs., (© 2022 Published by Elsevier Inc. on behalf of Asian Oncology Nursing Society.)

Background: Anxiety disorder is one of the most common mental health problems worldwide, including Malaysia, and this issue has gained concern and attention from many, including experts and authorities globally. While average levels of stress and worry may help to motivate students to perform well in their studies, excessive feelings will increase their level of anxiety., Methods: A cross-sectional study was conducted at selected government and private universities throughout Malaysia. A total of 1851 students participated in this study. The students were asked to complete self-administered questionnaires, including socio-demographic, academic, and psychosocial characteristics. The Generalized Anxiety Disorder-7 (GAD-7) questionnaire was used to measure the prevalence risk of anxiety among the students. Chi-square analysis was conducted to find the relationship between the variables and anxiety, and multivariate logistic regression analysis was used to identify the predictors., Results: The response rate was 97.90%, where 1821 out of 1860 students participated in the study. The prevalence risk of anxiety in this study was recorded at 29%. The data revealed that academic year, financial support for the study, alcohol consumption, poor sleep quality, body mass index (BMI), having a good friend in the university, having doubt regarding the future, actively involved in the society, and having problems with other students and lecturer(s) were significantly associated with risk of anxiety; with the academic year as the primary predictor., Conclusions: The findings highlight the current prevalence risk of anxiety among university students in Malaysia. The outcome of this study can serve as the evident baseline data and help with the development of specific interventions in addressing and managing the issue appropriately.

Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder, often persists into adulthood. In Malaysia, the prevalence rate of hyperactivity symptoms is highest among Chinese Malaysians. There are limited evidence-based treatment options targeting the core symptoms of ADHD, as well as executive functioning. In addition, conventional psychotherapeutic approaches for adults with ADHD have been found to be highly labor-intensive. The present study will evaluate the effectiveness of an online mindfulness-based intervention to reduce inattention and hyperactivity-impulsivity and improve executive functioning among Chinese Malaysian college emerging adults with ADHD. Informed by established literature, we will design an 8-week online mindfulness-based intervention (i.e., iMBI). We will conduct a two-arm randomized controlled trial comparing an iMBI plus treatment-as-usual group ( n = 54) and an enhanced treatment-as-usual control group ( n = 54). Outcome measures of inattention, hyperactivity-impulsivity, and executive functioning will be collected at baseline, immediately post-intervention, and 1-month post-intervention. The findings of the present study will not only demonstrate the implementation of iMBI as a new treatment modality but also inform practitioners on the effectiveness of iMBI in reducing the burden of adults living with ADHD.

Introduction: Pelvic floor muscle training (PFMT) strongly recommended to incontinent pregnant women. The Kegel Exercise Pregnancy Training-app trial is a multicentre cluster-randomised study aims to assess the effectiveness and its cost-effectiveness of the mobile app guidance in PFMT among incontinent pregnant women., Methods and Analysis: 370 pregnant women (aged 18 years old and above) will be recruited with International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form. Ten clusters (primary care clinics) will be randomly assigned to either PFMT or usual care in a 1:1 ratio by an independent researcher (sealed envelope). The primary outcome will be urinary incontinence, and the secondary outcomes (quality of life; PFMT adherence, psychological status and mobile apps' usability) will be assessed at four measurement time points (t0: baseline) and postintervention (t1: 4 weeks, t2: 8 weeks and t3: 8 weeks postnatal). T-test analysis will determine any significant differences at the baseline between the control and intervention groups. The mixed-model analysis will determine the effectiveness of the intervention at the population-average level for both the primary and secondary outcomes. For the cost-effectiveness analysis, expenditures during the study and 6 months after the intervention will be compared between the groups using the multiway sensitivity analysis. The recruitment planned will be in December 2020, and the planned end of the study will be in August 2021., Ethics and Dissemination: This study protocol was approved by the Ethics Committee for Research Involving Human Subjects, Universiti Putra Malaysia (JKEUPM-2019-368) and Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia, NMRR-19-412-47116 (IIR) with the ANZCTR registration. This study will obtain informed written consent from all the study participants. The results which conform with the Consolidated Standards of Reporting Trials and the Recommendations for Interventional Trials will be published for dissemination in peer-reviewed journals and conference proceedings., Trial Registration Number: ACTRN12619000379112., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

SRS27, an andrographolide analogue, had been proven to have therapeutic properties at a dose of 3 mg/kg in both in vitro and in vivo asthma models of our previous study. The present study focuses on the pharmacokinetic and toxicity profile of this compound to provide further evidence for the development of this compound as an anti-asthma agent. A simple pharmacokinetic study was performed in female BALB/c mice to measure blood plasma concentration of the compound at therapeutic dose. At a single dose of 3 mg/kg, SRS27 had a relatively short half-life but was able to achieve a concentration range of 13-19 μM that is related to its in vitro bioactivities. With regard to toxicity profile, SRS27 appears to be safe, as no histopathological changes were observed in the liver, kidneys and ovaries of SRS27-treated female BALB/c mice. In addition, there was no significant change in the mean body weight and organ weight of the animals in the SRS27-treated groups compared with the vehicle-treated control group at the end of the treatment. This fully supports the absence of any significant changes in peripheral blood leukocyte counts of SRS27-treated mice. Rewardingly, this acute toxicity study also revealed that SRS27 has a wide therapeutic window as no toxicity symptoms were detected with a dose up to 60 mg/kg daily when tested for 14 days. These results provide strong justification for further investigation of SRS27 as a potential new anti-asthma agent.

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.

Apicomplexan parasites include the causative agents of malaria and toxoplasmosis. Cell-based screens in Toxoplasma previously identified a chemical modulator of calcium signaling (ENH1) that blocked parasite egress from host cells and exhibited potent antiparasitic activity. To identify the targets of ENH1, we adapted thermal proteome profiling to Toxoplasma , which revealed calcium-dependent protein kinase 1 (CDPK1) as a target. We confirmed the inhibition of CDPK1 by ENH1 in vitro and in parasites by comparing alleles sensitive or resistant to ENH1. CDPK1 inhibition explained the block in egress; however, the effects of ENH1 on calcium homeostasis and parasite viability were CDPK1-independent, implicating additional targets. Thermal proteome profiling of lysates from parasites expressing the resistant allele of CDPK1 identified additional candidates associated with the mitochondria and the parasite pellicle-compartments that potentially function in calcium release and homeostasis. Our findings illustrate the promise of thermal profiling to identify druggable targets that modulate calcium signaling in apicomplexan parasites.

Limited evidence on the association of being bullied with depression among adolescents was found in Malaysia. This study aimed to determine the association of being bullied and depression among Malaysian school-going adolescents. Data from the National Health and Morbidity Survey 2017, a cross-sectional study conducted from March to May 2017, was analyzed using descriptive and multiple logistic regression analysis. A validated tool, the Depression, Anxiety, and Stress Scale-21 was used to categorize those with moderate or higher levels of depressive symptoms as having depression. A total of 27 399 school-going adolescents participated and 18.3% were found depressed. Adolescents of Indian ethnicity (adjusted odds ratio [aOR] = 2.02, P < .001), those with parents living apart (aOR = 1.41, P < .001), and those who were being bullied (aOR = 2.98, P < .001) were more likely to have depression. This study demonstrated the association between being bullied and having depression. Comprehensive preventive strategies should be implemented taking into consideration the findings from this study.

Toxoplasma can reach distant organs, especially the brain, leading to a lifelong chronic phase. However, genes involved in related in vivo processes are currently unknown. Here, we use focused CRISPR libraries to identify Toxoplasma genes that affect in vivo fitness. We focus on TgWIP, whose deletion affects Toxoplasma dissemination to distant organs. We show that TgWIP is secreted into the host cell upon invasion and interacts with the host WAVE regulatory complex and SHP2 phosphatase, both of which regulate actin dynamics. TgWIP affects the morphology of dendritic cells and mediates the dissolution of podosomes, which dendritic cells use to adhere to extracellular matrix. TgWIP enhances the motility and transmigration of parasitized dendritic cells, likely explaining its effect on in vivo fitness. Our results provide a framework for systemic identification of Toxoplasma genes with in vivo effects at the site of infection or on dissemination to distant organs, including the brain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Somatosensory feedback of the hand is essential for object identification. Without somatosensory feedback, individuals cannot reliably determine the size or compliance of an object. Electrical nerve stimulation can restore localized tactile and proprioceptive feedback with intensity discrimination capability similar to natural sensation. We hypothesized that adding artificial somatosensation improves object recognition accuracy when using a prosthesis. To test this hypothesis, we provided different forms of sensory feedback-tactile, proprioceptive, or both-to two subjects with upper limb loss. The subjects were asked to identify the size or mechanical compliance of different foam blocks placed in the prosthetic hand while visually and audibly blinded. During trials, we did not inform the subjects of their performance, but did ask them about their confidence in correctly identifying objects. Finally, we recorded applied pressures during object interaction. Subjects were free to use any strategy they chose to examine the objects. Object identification was most accurate with both tactile and proprioceptive feedback. The relative importance of each type of feedback, however, depended on object characteristics and task. Sensory feedback increased subject confidence and was directly correlated with accuracy. Subjects applied less pressure to the objects when they had tactile pressure feedback. Artificial somatosensory feedback improves object recognition and the relative importance of tactile versus proprioceptive feedback depends on the test set. We believe this test battery provides an effective means to assess the impact of sensory restoration and the relative contribution of different forms of feedback (tactile vs. kinesthetic) within the neurorehabilitation field., Competing Interests: The authors have declared that no competing interests exist.

Apicomplexan parasites, such as Toxoplasma gondii, cause extensive morbidity and mortality in humans and livestock, highlighting the need for a deeper understanding of their molecular biology. Although techniques for the generation of targeted gene disruptions have long been available for apicomplexans, such methods are not readily scalable to the entire genome. We recently used CRISPR-Cas9 to disrupt all nuclear protein-coding genes in T. gondii using a pooled format. The method relies on transfection of a guide RNA library into parasites constitutively expressing Cas9. Here, we present the complete workflow of such a screen, including preparation of the guide RNA library, growth and testing of the recipient strain, generation of the mutant population, culture conditions for the screen, preparation of genomic DNA libraries, next-generation sequencing of the guide RNA loci, and analysis to detect fitness-conferring genes. This method can be deployed to study how culture conditions affect the repertoire of genes needed by parasites, which will enable studies of their metabolic needs, host specificity, and drug-resistance mechanisms. In addition, by manipulating the background in which the screen is performed, researchers will be able to investigate genetic interactions, which may help uncover redundancy or epistasis in the parasite genome. Using this method, a genome-wide screen and its analysis can be completed in 3 weeks, after ∼1 month of preparation to generate the library and grow the cells needed, making it a powerful tool for uncovering functionally important genes in apicomplexan parasites.

Depression among adolescents is increasing and worrying because of its morbidity and mortality from suicide. It has been found to be associated with negative parental styles. The objective of this study was to determine the relationship between perceived negative parental styles and depressive symptoms among adolescents in Hulu Langat District, Selangor, Malaysia. A cross-sectional study was carried out on 1769 secondary school students by using a multistage cluster sampling method. Data were collected by using a set of validated, pre-tested and standardized questionnaires which included the Measures of Parental styles (MOPS) and modified Depression, Anxiety and Stress Scale 12 (DASS-12) for adolescents. Data were analyzed by using the chi-square test, Pearson's correlation coefficient and independent t-tests. Out of 1800, 1769 completed the questionnaire giving a response rate of 98.3%. The prevalence of severe depressive symptoms was about 14% while 18.0% and 36.1% of respondents have moderate and mild depressive symptoms, respectively. There were significantly moderate and positive correlations between perceived indifferent parents (Father: r = 0.367; Mother: r = 0.340, p < 0.05), perceived abusive parents (Father: r = 0.338; Mother: r = 0.331, p < 0.05) and depressive symptoms among the respondents. While perceived over control parents shows a significantly positive but weak correlation (Father: r = 0.206; Mother: r = 0.244, p < 0.05) with depressive symptoms among respondents. All types of parental styles in this study were significantly different among respondents with different categories of depressive symptoms (p < 0.008). Perceived negative parental styles have significant influence on adolescents' depressive symptoms. Intervention on modifying parental style is needed to reduce depressive symptoms.

Apicomplexan parasites are leading causes of human and livestock diseases such as malaria and toxoplasmosis, yet most of their genes remain uncharacterized. Here, we present the first genome-wide genetic screen of an apicomplexan. We adapted CRISPR/Cas9 to assess the contribution of each gene from the parasite Toxoplasma gondii during infection of human fibroblasts. Our analysis defines ∼200 previously uncharacterized, fitness-conferring genes unique to the phylum, from which 16 were investigated, revealing essential functions during infection of human cells. Secondary screens identify as an invasion factor the claudin-like apicomplexan microneme protein (CLAMP), which resembles mammalian tight-junction proteins and localizes to secretory organelles, making it critical to the initiation of infection. CLAMP is present throughout sequenced apicomplexan genomes and is essential during the asexual stages of the malaria parasite Plasmodium falciparum. These results provide broad-based functional information on T. gondii genes and will facilitate future approaches to expand the horizon of antiparasitic interventions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vaccines have had broad medical impact, but existing vaccine technologies and production methods are limited in their ability to respond rapidly to evolving and emerging pathogens, or sudden outbreaks. Here, we develop a rapid-response, fully synthetic, single-dose, adjuvant-free dendrimer nanoparticle vaccine platform wherein antigens are encoded by encapsulated mRNA replicons. To our knowledge, this system is the first capable of generating protective immunity against a broad spectrum of lethal pathogen challenges, including H1N1 influenza, Toxoplasma gondii, and Ebola virus. The vaccine can be formed with multiple antigen-expressing replicons, and is capable of eliciting both CD8(+) T-cell and antibody responses. The ability to generate viable, contaminant-free vaccines within days, to single or multiple antigens, may have broad utility for a range of diseases.

Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6-8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The life cycles of apicomplexan parasites progress in accordance with fluxes in cytosolic Ca(2+) Such fluxes are necessary for events like motility and egress from host cells. We used genetically encoded Ca(2+) indicators (GCaMPs) to develop a cell-based phenotypic screen for compounds that modulate Ca(2+) signaling in the model apicomplexan Toxoplasma gondii In doing so, we took advantage of the phosphodiesterase inhibitor zaprinast, which we show acts in part through cGMP-dependent protein kinase (protein kinase G; PKG) to raise levels of cytosolic Ca(2+) We define the pool of Ca(2+) regulated by PKG to be a neutral store distinct from the endoplasmic reticulum. Screening a library of 823 ATP mimetics, we identify both inhibitors and enhancers of Ca(2+) signaling. Two such compounds constitute novel PKG inhibitors and prevent zaprinast from increasing cytosolic Ca(2+) The enhancers identified are capable of releasing intracellular Ca(2+) stores independently of zaprinast or PKG. One of these enhancers blocks parasite egress and invasion and shows strong antiparasitic activity against T. gondii The same compound inhibits invasion of the most lethal malaria parasite, Plasmodium falciparum Inhibition of Ca(2+)-related phenotypes in these two apicomplexan parasites suggests that depletion of intracellular Ca(2+) stores by the enhancer may be an effective antiparasitic strategy. These results establish a powerful new strategy for identifying compounds that modulate the essential parasite signaling pathways regulated by Ca(2+), underscoring the importance of these pathways and the therapeutic potential of their inhibition., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Tobacco smoking is considered a risk factor for cervical cancer development due to the presence of tobacco based carcinogenic metabolites in cervical cells of female smokers. In this study, we investigated the role of the T3801C (MspI) polymorphism of CYP1A1, a gene encoding an enzyme necessary for the initiation of tobacco based carcinogen metabolism, on cervical cancer risk. The T to C substitution may alter CYP1A1 activities, potentially elevating cervical cancer risk. Since results of gene-disease association studies vary according to the study population, the multi-ethnic population of Malaysia provides an excellent representative cohort for identifying and comparing the cervical cancer risk among the 3 major ethnics in Southeast Asia in relation to CYP1A1 MspI polymorphism., Materials and Methods: A total of 195 Thin Prep Pap smear samples from HPV negative and cancer free females were randomly selected as controls while 106 formalin fixed paraffin embedded samples from females with invasive cervical cancer were randomly selected for the cases group. The polymorphisms were identified using restriction fragment length polymorphism (RFLP) PCR., Results: We found no significant associations between CYP1A1 MspI polymorphism and cervical cancer in the general Malaysian female population. However, upon ethnic stratification, the variant C/C genotype was significantly associated with a 4.66-fold increase in cervical cancer risk in Malay females (95% CI= 1.21-17.9; p=0.03). No significant association was observed in the Chinese and Indian females. Additionally, there were no significant associations in the dominant model and allele frequency model analysis in both the general and ethnically stratified female population of Malaysia., Conclusions: Our findings suggest that the C/C genotype of CYP1A1 MspI polymorphism is associated with the development of cervical carcinoma in the Malay females of Malaysia.