HMGB1 Stimulates Activity of Polymerase β on Nucleosome Substrates

The process of base excision repair (BER) recognizes and repairs small lesions or inappropriate bases on DNA through either a short-patch or long-patch pathway. The enzymes involved in BER have been well-characterized on DNA substrates, and, somewhat surprisingly, many of these enzymes, including several DNA glycosylases, AP endonuclease (APE), FEN1 endonuclease, and DNA ligases, have been shown to have activity on DNA substrates within nucleosomes. DNA polymerase β (Pol β), however, exhibits drastically reduced or no activity on nucleosomal DNA. Interestingly, acetylation of Pol β, by the acetyltransferase p300, inhibits its 5′ dRP-lyase activity and presumably pushes repair of DNA substrates through the long-patch base excision repair (LP-BER) pathway. In addition to the major enzymes involved in BER, a chromatin architectural factor, HMGB1, was found to directly interact with and enhance the activity of APE1 and FEN1, and thus may aid in altering the structure of the nucleosome to be more accessible to BER factors. In this work, we investigated whether acetylation of Pol β, either alone or in conjunction with HMGB1, facilitates its activity on nucleosome substrates. We find acetylated Pol β exhibits enhanced strand displacement synthesis activity on DNA substrates, but, similar to the unmodified enzyme, has little or no activity on nucleosomes. Preincubation of DNA templates with HMGB1 has little or no stimulatory effect on Pol β and even is inhibitory at higher concentrations. In contrast, preincubation of nucleosomes with HMGB1 rescues Pol β gap-filling activity in nucleosomes, suggesting that this factor may help overcome the repressive effects of chromatin

Pilot Study of a Resource-Appropriate Strategy for Downstaging Breast Cancer in Rural Uganda

Breast cancer incidence and mortality are rapidly increasing in low- and middle-income countries like Uganda. Shifting the proportion of women presenting with late-stage breast cancer to early-stage breast cancer (downstaging) at the time of diagnosis would substantially improve survival and efficient use of available resources. Imaging The World (ITW) conducted a pilot study in Uganda where trained village health teams (VHTs) promoted breast cancer awareness in the Kamuli District (Uganda). As a result, 212 women with self-detected lumps presented to the community health center level III (Nawanyago HCIII) for a clinical breast examination (CBE). Patients with masses on CBE were examined with breast ultrasound by a certified sonographer trained in breast imaging. Women with ultrasound-detected masses were referred to a regional health center for further evaluation. Of the 212 women, 44 (21%) had a palpable mass by CBE, 11 (28%) examined by ultrasound were recommended for biopsy, and four breast cancers were diagnosed. Providing ultrasound scanning at Nawanyago HCIII reduced the number of women travelling to the referral hospital by 75%. As a result of breast cancer awareness and ultrasound studies, we were able to diagnose breast cancer at an earlier stage than would be otherwise possible. This pilot project supports locally available breast ultrasound as a resource-appropriate strategy to downstage breast cancer in a low-income country

Using Village Health Teams for Effective Ultrasound Education in Rural Uganda

Maternal and child health conditions, many of which can be detected by ultrasound, represent the highest burden of disease in Uganda. Imaging the World (ITW) is a not-for-profit organization which integrates high quality, affordable ultrasound services into rural health facilities. Of all the challenges faced with implementation of ITW programs in Uganda, lack of sensitization to ultrasound represented the greatest barrier. The Village Health Team (VHT) is an existing public health “train the trainer” model sponsored by the Uganda Ministry of Health which provides public health training to community volunteers. Trained VHT members were recruited to help with ultrasound community outreach and education. These VHT members were successful in achieving dramatic community acceptance and increased utilization of ultrasound services in rural communities. This has led to significant contributions in improving population health in low-resource settings

SARS-CoV-2 seroprevalence and implications for population immunity: Evidence from two Health and Demographic Surveillance System sites in Kenya, February-December 2022.

BACKGROUND: We sought to estimate SARS-CoV-2 antibody seroprevalence within representative samples of the Kenyan population during the third year of the COVID-19 pandemic and the second year of COVID-19 vaccine use. METHODS: We conducted cross-sectional serosurveys among randomly selected, age-stratified samples of Health and Demographic Surveillance System (HDSS) residents in Kilifi and Nairobi. Anti-spike (anti-S) immunoglobulin G (IgG) serostatus was measured using a validated in-house ELISA and antibody concentrations estimated with reference to the WHO International Standard for anti-SARS-CoV-2 immunoglobulin. RESULTS: HDSS residents were sampled in February-June 2022 (Kilifi HDSS N = 852; Nairobi Urban HDSS N = 851) and in August-December 2022 (N = 850 for both sites). Population-weighted coverage for ≥1 doses of COVID-19 vaccine were 11.1% (9.1-13.2%) among Kilifi HDSS residents by November 2022 and 34.2% (30.7-37.6%) among Nairobi Urban HDSS residents by December 2022. Population-weighted anti-S IgG seroprevalence among Kilifi HDSS residents increased from 69.1% (65.8-72.3%) by May 2022 to 77.4% (74.4-80.2%) by November 2022. Within the Nairobi Urban HDSS, seroprevalence by June 2022 was 88.5% (86.1-90.6%), comparable with seroprevalence by December 2022 (92.2%; 90.2-93.9%). For both surveys, seroprevalence was significantly lower among Kilifi HDSS residents than among Nairobi Urban HDSS residents, as were antibody concentrations (p < 0.001). CONCLUSION: More than 70% of Kilifi residents and 90% of Nairobi residents were seropositive for anti-S IgG by the end of 2022. There is a potential immunity gap in rural Kenya; implementation of interventions to improve COVID-19 vaccine uptake among sub-groups at increased risk of severe COVID-19 in rural settings is recommended

Doctor of Philosophy

dissertationResearch indicates that culturally determined beliefs and values play a significant role in influencing perinatal healthcare access and utilization among Somali refugee women resettled in the U.S. The purpose of this qualitative descriptive study was to explore the practices of resettled Somali refugee women around pregnancy, to explore the cultural gaps between the women and healthcare providers, and to identify their perception of barriers in accessing and utilizing perinatal services in Salt Lake City, Utah. This study utilized a qualitative descriptive (interpretive description) method of inquiry to analytically inquire about the cultural descriptions and experiences of Somali refugee women as narrated by themselves. Data collection methods used in this study included interviews, field notes and observation. Recruitment of study participants began September 2016 concluding in April 2017. Leininger's Theory of Culture, Care Diversity and Universality and Ramsden's Cultural Safety theory both served as theoretical frameworks that helped shape the conception of culture and interpretation of data that emerged from interviews. Fifteen individual interviews were recorded independently and transcribed. The data were coded and labeled according to content and concepts. The emergent codes were organized based on similarity, salience or relevance leading to emergent concepts, subthemes and themes. Results describe the symbolism of Somali refugee women living in two separate worlds and their resulting state of in-betweenness. The cultural context in which Somali iv refugee women approached, managed, and conceptualized pregnancy and childbirth is also described. The results also captured significant external influences that affected the women's perinatal healthcare decisions as well as their own descriptions of their experiences and perceptions with Western perinatal healthcare. Recommendations from the women on how to bridge the cultural gaps as well as implications of this work are identified. These include better perinatal healthcare practices by Western healthcare providers, increased cultural competence and provision of culturally safe care. When Western healthcare providers ignore or are unfamiliar with the cultural beliefs of refugee women patients, it can lead to inadvertent consequences such as medication errors, breakdown in care, noncompliance with care plans, lack of or reduced utilization of care, and overall patient dissatisfaction

To Investigate or Not To Investigate?: The Reality of The Prosecutor’s Proprio Motu Powers Under The Rome Statute

To Investigate or Not To Investigate?: The Reality of The Prosecutor’s Proprio Motu Powers Under The Rome Statute The Honorable Magistrate Angela Njeri Thuku, Resident Magistrate, Kenyan Judiciary; Co-editor, Kenya Magistrates and Judges Association’s Magazine “Hakimu”; Fellow, 2011-2012 Golden Gate University School of Law/International Women Judges Graduate Fellowship Program (LL.M. in International Legal Studies)

To Investigate or Not To Investigate?: The Reality of The Prosecutor’s Proprio Motu Powers Under The Rome Statute

To Investigate or Not To Investigate?: The Reality of The Prosecutor’s Proprio Motu Powers Under The Rome Statute The Honorable Magistrate Angela Njeri Thuku, Resident Magistrate, Kenyan Judiciary; Co-editor, Kenya Magistrates and Judges Association’s Magazine “Hakimu”; Fellow, 2011-2012 Golden Gate University School of Law/International Women Judges Graduate Fellowship Program (LL.M. in International Legal Studies)