Household and climate factors influence Aedes aegypti presence in the arid city of Huaquillas, Ecuador

Funding: This study was funded by NSF EEID DEB 1518681 to SJR, EAM, AMS. EAM was also supported by NIH R35GM133439, NSF DEB-2011147, the Terman Award, the Helman Faculty Fellowship, and the Stanford Center for Innovation in Global Health.Arboviruses transmitted by Aedes aegypti (e.g., dengue, chikungunya, Zika) are of major public health concern on the arid coastal border of Ecuador and Peru. This high transit border is a critical disease surveillance site due to human movement-associated risk of transmission. Local level studies are thus integral to capturing the dynamics and distribution of vector populations and social-ecological drivers of risk, to inform targeted public health interventions. Our study examines factors associated with household-level Ae. aegypti presence in Huaquillas, Ecuador, while accounting for spatial and temporal effects. From January to May of 2017, adult mosquitoes were collected from a cohort of households (n = 63) in clusters (n = 10), across the city of Huaquillas, using aspirator backpacks. Household surveys describing housing conditions, demographics, economics, travel, disease prevention, and city services were conducted by local enumerators. This study was conducted during the normal arbovirus transmission season (January-May), but during an exceptionally dry year. Household level Ae. aegypti presence peaked in February, and counts were highest in weeks with high temperatures and a week after increased rainfall. Univariate analyses with proportional odds logistic regression were used to explore household social-ecological variables and female Ae. aegypti presence. We found that homes were more likely to have Ae. aegypti when households had interruptions in piped water service. Ae. aegypti presence was less likely in households with septic systems. Based on our findings, infrastructure access and seasonal climate are important considerations for vector control in this city, and even in dry years, the arid environment of Huaquillas supports Ae. aegypti breeding habitat.Publisher PDFPeer reviewe

Nonlinear and delayed impacts of climate on dengue risk in Barbados: A modelling study

Background: Over the last 5 years (2013–2017), the Caribbean region has faced an unprecedented crisis of co-occurring epidemics of febrile illness due to arboviruses transmitted by the Aedes sp. mosquito (dengue, chikungunya, and Zika). Since 2013, the Caribbean island of Barbados has experienced 3 dengue outbreaks, 1 chikungunya outbreak, and 1 Zika fever outbreak. Prior studies have demonstrated that climate variability influences arbovirus transmission and vector population dynamics in the region, indicating the potential to develop public health interventions using climate information. The aim of this study is to quantify the nonlinear and delayed effects of climate indicators, such as drought and extreme rainfall, on dengue risk in Barbados from 1999 to 2016. Methods and findings: Distributed lag nonlinear models (DLNMs) coupled with a hierarchal mixed-model framework were used to understand the exposure–lag–response association between dengue relative risk and key climate indicators, including the standardised precipitation index (SPI) and minimum temperature (Tmin). The model parameters were estimated in a Bayesian framework to produce probabilistic predictions of exceeding an island-specific outbreak threshold. The ability of the model to successfully detect outbreaks was assessed and compared to a baseline model, representative of standard dengue surveillance practice. Drought conditions were found to positively influence dengue relative risk at long lead times of up to 5 months, while excess rainfall increased the risk at shorter lead times between 1 and 2 months. The SPI averaged over a 6-month period (SPI-6), designed to monitor drought and extreme rainfall, better explained variations in dengue risk than monthly precipitation data measured in millimetres. Tmin was found to be a better predictor than mean and maximum temperature. Furthermore, including bidimensional exposure–lag–response functions of these indicators—rather than linear effects for individual lags—more appropriately described the climate–disease associations than traditional modelling approaches. In prediction mode, the model was successfully able to distinguish outbreaks from nonoutbreaks for most years, with an overall proportion of correct predictions (hits and correct rejections) of 86% (81%:91%) compared with 64% (58%:71%) for the baseline model. The ability of the model to predict dengue outbreaks in recent years was complicated by the lack of data on the emergence of new arboviruses, including chikungunya and Zika. Conclusion: We present a modelling approach to infer the risk of dengue outbreaks given the cumulative effect of climate variations in the months leading up to an outbreak. By combining the dengue prediction model with climate indicators, which are routinely monitored and forecasted by the Regional Climate Centre (RCC) at the Caribbean Institute for Meteorology and Hydrology (CIMH), probabilistic dengue outlooks could be included in the Caribbean Health-Climatic Bulletin, issued on a quarterly basis to provide climate-smart decision-making guidance for Caribbean health practitioners. This flexible modelling approach could be extended to model the risk of dengue and other arboviruses in the Caribbean region

Micronúcleos y otras anormalidades nucleares en células de mucosa bucal como biomarcadores de genotoxicidad y citotoxicidad en personal expuesto a gases anestésicos

Associated damage to health during occupational exposition is a controvert issue. It has been reported either reproductive toxicity, affections to organs, cancer and genotoxicity. Objective: To evaluate micronuclei and other nuclear abnormalities frequencies at epithelial mouth cells from people exposed to anesthetic gasses as genotoxicity and cytotoxicity markers. Methodology: We gathered a total of 164 epithelial mouth samples from 81 anesthesiologists from different Mexican Health clinics across, 43 health people not exposed and with no addictions and 40 patients receiving antineoplastic drugs. The survey included questions related with habits, work location and schedules and general data that could be related with results. Epithelial cell smears were obtained with gentle scraping, dried and fixed with 80% ethylic alcohol and stained with orcein and fast green. We analyzed 2,000 cells from each sample under microscope (100x) and counted for Micronucleated cells (CMN) and Nuclear abnormalities (AN) [Binucleated (CBN), Lobulated nucleus (NL), Karyorrhexis (CR), condensed chromatin (CC), Pyknosis (PN) and Karyolysis (CL)]. Results: Counts from anesthesiologists MN were statistically higher than not exposed [2.8(1.9)/ 0.7(0.7)/ 1,000 cells, (p: <0.001)]. No matter of exposition time, age or sex, 86% of the anesthesiologists presented micronucleus genotoxicity and the complement presented cytotoxicity. Conclusions: Occupational exposition to anesthetic gases at Mexican health clinics system induces genotoxic and cytotoxic damage been evident by the MN and AN count at mouth epithelial cells. We highly recommend increasing security measures.El daño a la salud asociado a exposición ocupacional de anestésicos es controversial, se ha encontrado toxicidad reproductiva, afección de órganos, cáncer y genotoxicidad. Objetivo: Evaluar la frecuencia de micronúcleos y otras anormalidades nucleares en células de mucosa bucal de personal expuesto a gases, como marcadores de genotoxicidad y citotoxicidad. Métodología: Se colectaron 164 muestras de mucosa bucal de 81 anestesiólogos que laboraban en diferentes hospitales en México, 43 personas sanas no expuestas y sin toxicomanías, y 40 pacientes tratados con antineoplásicos. Se preguntó hábitos, lugar y horas de trabajo, sistemas de eliminación de gases del centro de trabajo y datos que podrían influir en los resultados. Se realizaron frotis de mucosa bucal mediante un raspado suave, se dejaron secar, se fijaron con etanol al 80% y se tiñeron con orceína y verde rápido. Al microscopio (100X), por muestra se analizaron 2,000 células, se identificaron células micronucleadas (CMN) y anormaliades nucleares (AN) [binucleadas (CBN), núcleo lobulado (NL), cariorrexis (CR), cromatina condensada (CC), picnosis (PN) y cariólisis (CL)]. Resultados: La frecuencia de CMN es mayor en anestesiólogos que en no expuestos, [2.8 (1.9)/ 0.7(0.7)/ 1,000 células, (p: <0.001)]. Independiente de tiempo de exposición, lugar de trabajo, edad o sexo, en el 86.4% de anestesiólogos se observó micronucleogenicidad y en el resto citotoxicidad. Conclusiones: La exposición ocupacional a gases anestésicos en el ambiente hospitalario mexicano induce daño genotóxico y citotóxico evidenciado por presencia de MN y AN en células exfoliadas de mucosa bucal, por ello se sugiere reforzar las medidas de seguridad

High-efficiency genome editing via 2A-coupled co-expression of fluorescent proteins and zinc finger nucleases or CRISPR/Cas9 nickase pairs

Targeted endonucleases including zinc finger nucleases (ZFNs) and clustered regularly interspaced short palindromic repeats (CRISPRs)/Cas9 are increasingly being used for genome editing in higher species. We therefore devised a broadly applicable and versatile method for increasing editing efficiencies by these tools. Briefly, 2A peptide-coupled co-expression of fluorescent protein and nuclease was combined with fluorescence-activated cell sorting (FACS) to allow for efficient isolation of cell populations with increasingly higher nuclease expression levels, which translated into increasingly higher genome editing rates. For ZFNs, this approach, combined with delivery of donors as single-stranded oligodeoxynucleotides and nucleases as messenger ribonucleic acid, enabled high knockin efficiencies in demanding applications, including biallelic codon conversion frequencies reaching 30–70% at high transfection efficiencies and ∼2% at low transfection efficiencies, simultaneous homozygous knockin mutation of two genes with ∼1.5% efficiency as well as generation of cell pools with almost complete codon conversion via three consecutive targeting and FACS events. Observed off-target effects were minimal, and when occurring, our data suggest that they may be counteracted by selecting intermediate nuclease levels where off-target mutagenesis is low, but on-target mutagenesis remains relatively high. The method was also applicable to the CRISPR/Cas9 system, including CRISPR/Cas9 mutant nickase pairs, which exhibit low off-target mutagenesis compared to wild-type Cas9

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads

Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes

The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies

Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer

Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER+) breast cancer development, but estrogen receptor–negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER− mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers

Co-learning during the co-creation of a dengue early warning system for the health sector in Barbados

Over the past decade, the Caribbean region has been challenged by compound climate and health hazards, including tropical storms, extreme heat and droughts and overlapping epidemics of mosquito-borne diseases, including dengue, chikungunya and Zika. Early warning systems (EWS) are a key climate change adaptation strategy for the health sector. An EWS can integrate climate information in forecasting models to predict the risk of disease outbreaks several weeks or months in advance. In this article, we share our experiences of co-learning during the process of co-creating a dengue EWS for the health sector in Barbados, and we discuss barriers to implementation as well as key opportunities. This process has involved bringing together health and climate practitioners with transdisciplinary researchers to jointly identify needs and priorities, assess available data, co-create an early warning tool, gather feedback via national and regional consultations and conduct trainings. Implementation is ongoing and our team continues to be committed to a long-term process of collaboration. Developing strong partnerships, particularly between the climate and health sectors in Barbados, has been a critical part of the research and development. In many countries, the national climate and health sectors have not worked together in a sustained or formal manner. This collaborative process has purposefully pushed us out of our comfort zone, challenging us to venture beyond our institutional and disciplinary silos. Through the co-creation of the EWS, we anticipate that the Barbados health system will be better able to mainstream climate information into decision-making processes using tailored tools, such as epidemic forecast reports, risk maps and climate-health bulletins, ultimately increasing the resilience of the health system