Design and Synthesis of NIR BODIPY Dyes: Application for In Vivo Fluorescence Imaging and Photodynamic Therapy

DESIGN AND SYNTHESIS OF NIR BODIPY DYES: APPLICATION FOR IN VIVO FLUORESCENCE IMAGING AND PHOTODYNAMIC THERAPYSAMUEL G. AWUAH2012Photodynamic therapy (PDT) and fluorescence imaging are non-invasive modalities for disease treatment and diagnosis respectively. Both modalities require the use of a dye (light harvesting material) and light or source of excitation. In the case of PDT a sensitizer is needed while a fluorophore is used in the case of fluorescence imaging. PDT in addition to a sensitizer and light thrives on oxygen to generate a key cytotoxic species known as singlet oxygen. PDT has shown promise in the clinic for the treatment of surface cancers and age-macular degeneration. Fluorescence imaging on the other hand has a long history for in vitro use but a growing interest for in vivo preclinical and clinical use for diagnosis, particularly in malignancies, angiography and neurobiology. Fluorescence imaging due to its sensitivity, relatively low cost and less toxicity makes it reliable. The need to improve PDT and imaging heavily relies on the effectiveness of the sensitizer or imaging probe/fluorophore. Near infra-red (NIR) sensitizer/probes with a potential to target specific sites of interest could change the paradigm in the non-invasive modalities.In this dissertation, the design and synthesis of NIR BODIPY for use as photosensitizers and fluorescent probes was explored. We followed a synthetic strategy of incorporating heavy atoms in the BODIPY chromophore to obtain effective singlet oxygen generating BODIPY without compromising on their optical and photophysical properties with an added advantage of red-shifting to the NIR region. We further developed a robust but versatile strategy for building fluorescent molecular probes spanning the entire therapeutic window with potential for optical imaging. We then explored the capacity to functionalize these NIR dyes for potential targeting to vectors such as peptides, antibodies, etc. We also investigated the ability of representative dyes to induce photodynamic response and to serve as optical contrast agents

Mild Deprotection of the \u3cem\u3eN-Tert\u3c/em\u3e-Butyloxycarbonyl (\u3cem\u3eN\u3c/em\u3e-Boc) Group Using Oxalyl Chloride

We report a mild method for the selective deprotection of the N-Boc group from a structurally diverse set of compounds, encompassing aliphatic, aromatic, and heterocyclic substrates by using oxalyl chloride in methanol. The reactions take place under room temperature conditions for 1–4 h with yields up to 90%. This mild procedure was applied to a hybrid, medicinally active compound FC1, which is a novel dual inhibitor of IDO1 and DNA Pol gamma. A broader mechanism involving the electrophilic character of oxalyl chloride is postulated for this deprotection strategy

An evidence-based guide to the efficacy and safety of isometric resistance training in hypertension and clinical implications.

More than 30 randomized controlled trials, supported by individual patient-level and group-level meta-analyses and a Delphi analysis of expert opinion, unequivocally show isometric resistance training (IRT) elicits antihypertensive benefits in healthy people and those with chronic illness. We aim to provide efficacy and safety evidence, and a guide for IRT prescription and delivery. Recommendations are made for the use of IRT in specific patient populations and appropriate methods for IRT delivery. Published data suggest IRT consistently elicits mean blood pressure reductions of 7.4/3.3 mmHg systolic blood pressure/diastolic blood pressure, equivalent to antihypertensive medication monotherapy. Blood pressure reductions of this size are associated with an approximate 13% to 22% reduction in major cardiovascular events. Moreover, IRT is safe in a range of patient populations. We suggest that IRT has the greatest potential benefit when used as an antihypertensive therapy in individuals unwilling and/or unable to complete aerobic exercise, or who have had limited adherence or success with it; individuals with resistant or uncontrolled hypertension, already taking at least two pharmacological antihypertensive agents; and healthy or clinical populations, as an adjunct to aerobic exercise and dietary intervention in those who have not yet attained control of their hypertension. IRT is efficacious and produces clinically meaningful blood pressure reductions (systolic blood pressure, 7 mmHg; diastolic blood pressure, 3 mmHg). IRT is safe and typical program delivery requires only about 17 min weekly. IRT should be used as an adjunct to other exercise modalities, in people unable to complete other types of exercise, or in resistant hypertension. [Abstract copyright: © 2023. The Author(s).

Probabilistic Mapping and Spatial Pattern Analysis of Grazing Lawns in Southern African Savannahs Using WorldView-3 Imagery and Machine Learning Techniques

Savannah grazing lawns are a key food resource for large herbivores such as blue wildebeest (Connochaetes taurinus), hippopotamus (Hippopotamus amphibius) and white rhino (Ceratotherium simum), and impact herbivore densities, movement and recruitment rates. They also exert a strong influence on fire behaviour including frequency, intensity and spread. Thus, variation in grazing lawn cover can have a profound impact on broader savannah ecosystem dynamics. However, knowledge of their present cover and distribution is limited. Importantly, we lack a robust, broad-scale approach for detecting and monitoring grazing lawns, which is critical to enhancing understanding of the ecology of these vital grassland systems. We selected two sites in the Lower Sabie and Satara regions of Kruger National Park, South Africa with mesic and semiarid conditions, respectively. Using spectral and texture features derived from WorldView-3 imagery, we (i) parameterised and assessed the quality of Random Forest (RF), Support Vector Machines (SVM), Classification and Regression Trees (CART) and Multilayer Perceptron (MLP) models for general discrimination of plant functional types (PFTs) within a sub-area of the Lower Sabie landscape, and (ii) compared model performance for probabilistic mapping of grazing lawns in the broader Lower Sabie and Satara landscapes. Further, we used spatial metrics to analyse spatial patterns in grazing lawn distribution in both landscapes along a gradient of distance from waterbodies. All machine learning models achieved high F-scores (F1) and overall accuracy (OA) scores in general savannah PFTs classification, with RF (F1 = 95.73±0.004%, OA = 94.16±0.004%), SVM (F1 = 95.64±0.002%, OA = 94.02±0.002%) and MLP (F1 = 95.71±0.003%, OA = 94.27±0.003%) forming a cluster of the better performing models and marginally outperforming CART (F1 = 92.74±0.006%, OA = 90.93±0.003%). Grazing lawn detection accuracy followed a similar trend within the Lower Sabie landscape, with RF, SVM, MLP and CART achieving F-scores of 0.89, 0.93, 0.94 and 0.81, respectively. Transferring models to the Satara landscape however resulted in relatively lower but high grazing lawn detection accuracies across models (RF = 0.87, SVM = 0.88, MLP = 0.85 and CART = 0.75). Results from spatial pattern analysis revealed a relatively higher proportion of grazing lawn cover under semiarid savannah conditions (Satara) compared to the mesic savannah landscape (Lower Sabie). Additionally, the results show strong negative correlation between grazing lawn spatial structure (fractional cover, patch size and connectivity) and distance from waterbodies, with larger and contiguous grazing lawn patches occurring in close proximity to waterbodies in both landscapes. The proposed machine learning approach provides a novel and robust workflow for accurate and consistent landscape-scale monitoring of grazing lawns, while our findings and research outputs provide timely information critical for understanding habitat heterogeneity in southern African savannah

Synthesis, Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]\u3csup\u3e+\u3c/sup\u3e Complexes

Herein is reported the synthesis of two Au(III) complexes bearing the (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (R,R-QuinoxP*) or (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (S,S-QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl4.3H2O to one equivalent of the corresponding QuinoxP* ligand, (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (1) and (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) were formed, respectively, in moderate yields. The structure of (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC50 values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers (1 and 2) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes

Synthesis and Characterization of \u3cem\u3ed\u3c/em\u3e\u3csub\u3e5\u3c/sub\u3e-Barbarin for Use in Barbarin-Related Research

Based on structural similarities and equine administration experiments, Barbarin, 5-phenyl-2-oxazolidinethione from Brassicaceae plants, is a possible source of equine urinary identifications of aminorex, (R,S)-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, an amphetamine-related US Drug Enforcement Administration (DEA) controlled substance considered illegal in sport horses. We now report the synthesis and certification of d5-barbarin to facilitate research on the relationship between plant barbarin and such aminorex identifications. D5-barbarin synthesis commenced with production of d5-2-oxo-2-phenylacetaldehyde oxime (d5-oxime) from d5-acetophenone via butylnitrite in an ethoxide/ethanol solution. This d5-oxime was then reduced with lithium aluminum hydride (LiAlH4) to produce the corresponding d5-2-amino-1-phenylethan-1-ol (d5-phenylethanolamine). Final ring closure of the d5-phenylethanolamine was performed by the addition of carbon disulfide (CS2) with pyridine. The reaction product was purified by recrystallization and presented as a stable white crystalline powder. Proton NMR spectroscopy revealed a triplet at 5.88 ppm for one proton, a double doublet at 3.71 ppm for one proton, and double doublet at 4.11 ppm for one proton, confirming d5-barbarin as the product. Further characterization by high resolution mass spectrometry supports the successful synthesis of d5-barbarin. Purity of the recrystallized product was ascertained by High Performance Liquid Chromatography (HPLC) to be greater than 98%. Together, we have developed the synthesis and full characterization of d5-barbarin for use as an internal standard in barbarin-related and equine forensic research

Providing insight into the incubation period of Mycobacterium ulcerans disease: two case reports.

BACKGROUND: Buruli ulcer caused by Mycobacterium ulcerans is endemic in parts of West Africa and is most prevalent among the 5-15 years age group; Buruli ulcer is uncommon among neonates. The mode of transmission and incubation period of Buruli ulcer are unknown. We report two cases of confirmed Buruli ulcer in human immunodeficiency virus-unexposed, vaginally delivered term neonates in Ghana. CASE PRESENTATION: Patient 1: Two weeks after hospital delivery, a baby born to natives of the Ashanti ethnic group of Ghana was noticed by her mother to have a papule with associated edema on the right anterior chest wall and neck that later ulcerated. There was no restriction of neck movements. The diagnosis of Buruli ulcer was confirmed on the basis of a swab sample that had a positive polymerase chain reaction result for the IS2404 repeat sequence of M. ulcerans. Patient 2: This patient, from the Ashanti ethnic group in Ghana, had the mother noticing a swelling in the baby's left gluteal region 4 days after birth. The lesion progressively increased in size to involve almost the entire left gluteal region. Around the same time, the mother noticed a second, smaller lesion on the forehead and left side of neck. The diagnosis of Buruli ulcer was confirmed by polymerase chain reaction when the child was aged 4 weeks. Both patients 1 and 2 were treated with oral rifampicin and clarithromycin at recommended doses for 8 weeks in addition to appropriate daily wound dressing, leading to complete healing. Our report details two cases of polymerase chain reaction-confirmed Buruli ulcer in children whose lesions appeared at ages 14 and 4 days, respectively. The mode of transmission of M. ulcerans infection is unknown, so the incubation period is difficult to estimate and is probably dependent on the infective dose and the age of exposure. In our study, lesions appeared 4 days after birth in patient 2. Unless the infection was acquired in utero, this would be the shortest incubation period ever recorded. CONCLUSIONS: Buruli ulcer should be included in the differential diagnosis of neonates who present with characteristic lesions. The incubation period of Buruli ulcer in neonates is probably shorter than is reported for adults

Smallholder farmers’ perception of climatic and socio-economic factors influencing livelihoods in the transition zone of Ghana

Background: The study analyzed smallholder farmers’ perception with regards to climatic and socio-economic changes influencing their agriculture livelihoods and coping strategies thereof in the transition zone of Ghana. Methods: We used semi-structured questionnaires for household survey involving 59 households and focus group discussions (n=60) for data collection in three communities. Results: Farming systems are influenced by high and extreme temperatures, delayed onsets of rain, short raining season as well as unpredictable raining seasons. Similarly, socioeconomic factors affecting the communities and their households’ livelihood included i) bad road network; ii) high prices of farm inputs; iii) prevalent crop pests and diseases and iv) absence of irrigation facilities. It was ascertained that though most farmers have not made conscious efforts to adapt strategies in their farming system to climate change and the social stressors, as expressed in ‘doing nothing or bearing losses’ and we are at the ‘mercy’ of the weather, there are hidden resilience mechanisms that can be harnessed to strengthen their adaptation capabilities. Women in the study area have adapted to the changes in the weather and safeguarded against post-harvest loss of cassava more effectively as compared to their male counterparts. Similarly, the prevailing group farming and maintenance structure (locally known as ‘Noboa’) strengthen the shared responsibility and reciprocity among migrant’ farmers. Conclusions: Though these agrarian communities have some coping strategies to overcome some climatic and socioeconomic challenges, their general adaptive capacity in terms of physical, financial and human assets are limited. This, therefore, calls for the capacity building of both men and women on best farming practices, adaptation strategies and piloting of irrigation systems to enhance their major livelihood but these must be complemented with good road network for ease of access to the market centres

Evaluation of equity in informal land development systems in two Nigerian cities

The informal land development system in Sub-Saharan Africa (SSA) is perceived to promote equity and could be leveraged to support sustainable urban development and management. However, scanty empirical evidence exists on the extent of the system’s provision of equity to support policy formulation and practice in the region. Based on stakeholder workshops, focus group discussions and questionnaire surveys, this study analyses the system’s provision of equity in Nigeria. The study finds all categories of people undertake informal developments. Consistent with literature, this finding reflects wide patronage of the informal land development system and its relevance. Nevertheless, contrary to the existing perception, the system’s provision of equity is low. The study recommends for the institution of pro-poor and gender sensitive land development and management policies and programmes to increase the levels of equity to support the achievement of the country’s sustainable urban development and management agenda

Expression of aldehyde dehydrogenase 1 as a marker of mammary stem cells in benign and malignant breast lesions of Ghanaian women

BACKGROUND: Breast cancers that are negative for the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 (human epidermal growth factor receptor 2) marker are more prevalent among African women, and the biologically aggressive nature of these triple‐negative breast cancers (TNBCs) may be attributed to their mammary stem cell features. Little is known about expression of the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) in African women. Novel data are reported regarding ALDH1 expression in benign and cancerous breast tissue of Ghanaian women. METHODS: Formalin‐fixed, paraffin‐embedded specimens were transported from the Komfo Anoyke Teaching Hospital in Kumasi, Ghana to the University of Michigan for centralized histopathology study. Expression of ER, PR, HER2, and ALDH1 was assessed by immunohistochemistry. ALDH1 staining was further characterized by its presence in stromal versus epithelial and/or tumor components of tissue. RESULTS: A total of 173 women contributed to this study: 69 with benign breast conditions, mean age 24 years, and 104 with breast cancer, mean age 49 years. The proportion of benign breast conditions expressing stromal ALDH1 (n = 40, 58%) was significantly higher than those with cancer (n = 44, 42.3%) ( P = .043). Among the cancers, TNBC had the highest prevalence of ALDH1 expression, either in stroma or in epithelial cells. More than 2‐fold higher likelihood of ALDH1 expression was observed in TNBC cases compared with other breast cancer subtypes (odds ratio = 2.38, 95% confidence interval 1.03‐5.52, P = .042). CONCLUSIONS: ALDH1 expression was higher in stromal components of benign compared with cancerous lesions. Of the ER‐, PR‐, and HER2‐defined subtypes of breast cancer, expression of ALDH1 was highest in TNBC. Cancer 2013. © 2012 American Cancer Society. Mammary stem cells, as identified by cells expressing the marker aldehyde dehydrogenase 1 (ALDH1), appear to be correlated with malignant transformation and progression of breast tissue into biologically aggressive phenotypes. This study reveals increased expression of ALDH1 in benign and malignant tissue of women from the western sub‐Saharan African nation of Ghana, a population known to have higher frequency of triple‐negative breast cancer, and ALDH1 expression in the malignant specimens was found to be associated with risk of triple‐negative breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96403/1/27737_ftp.pd