Aberrant monomethylation of histone H4 lysine 20 activates the DNA damage checkpoint in Drosophila melanogaster

PR-Set7 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (K20) and is essential for cell proliferation. Our results show that in PR-Set7 mutants, the DNA damage checkpoint is activated. This phenotype is manifested by reduction in both the mitotic and the S phase indexes, a delay in the progression through early mitosis, and strong reduction of cyclin B. Furthermore, in a double mutant of PR-Set7 and mei-41 (the fly ATR orthologue), the abnormalities of mitotic progression and the cyclin B protein level were rescued. PR-Set7 also showed a defect in chromosome condensation that was enhanced in the double mutant. We therefore propose that monomethylated H4K20 is involved in the maintenance of proper higher order structure of DNA and is consequently essential for chromosome condensation

Interview with Dave Steward: Commonwealth Oral History Project

Interview with Dave Steward, conducted 17th April 2013 as part of the Commonwealth Oral History Project. The project aims to produce a unique digital research resource on the oral history of the Commonwealth since 1965 through sixty oral history interviews with leading figures in the recent history of the organisation. It will provide an essential research tool for anyone investigating the history of the Commonwealth and will serve to promote interest in and understanding of the organisation. Biography: Steward, Dave. 1945- . Born in Nairobi, Kenya. Educated at the University of Stellenbosch, 1962-65. Joined the South African Department of Foreign Affairs in 1966. Ambassador to the United Nations in New York, 1981-82. Policy Adviser on Southwest Africa/Namibia/Angola, 1983-85. Head, South African Communication Service, 1986-92. Director-General, Office of the South African President, 1992-94. Executive Director of the FW de Klerk Foundation, 1999- . Managing Director, Canopus Consultancies, 1997-

Crosstalk between the actin cytoskeleton and Ran-mediated nuclear transport

BACKGROUND: Transport of macromolecules into and out of the nucleus is a highly regulated process. The RanGTP/RanGDP gradient controls the trafficking of molecules exceeding the diffusion limit of the nuclear pore across the nuclear envelope. RESULTS: We found genetic interaction between genes establishing the Ran gradient, nuclear transport factor 2 (ntf-2), Ran GTPase activating protein (Sd), and the gene encoding Drosophila Profilin, chickadee (chic). The severe eye phenotype caused by reduction of NTF2 is suppressed by loss of function mutations in chic and gain of function mutations in Sd (RanGAP). We show that in chic mutants, as in Sd-RanGAP, nuclear export is impaired. CONCLUSION: Our data suggest that Profilin and the organization of the actin cytoskeleton play an important role in nuclear trafficking

The Histone H4 Lysine 20 Monomethyl Mark, Set by PR-Set7 and Stabilized by L(3)mbt, Is Necessary for Proper Interphase Chromatin Organization

Drosophila PR-Set7 or SET8 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (H4K20). L(3)MBT has been identified as a reader of methylated H4K20. It contains several conserved domains including three MBT repeats binding mono- and dimethylated H4K20 peptides. We find that the depletion of PR-Set7 blocks de novo H4K20me1 resulting in the immediate activation of the DNA damage checkpoint, an increase in the size of interphase nuclei, and drastic reduction of cell viability. L(3)mbt on the other hand stabilizes the monomethyl mark, as L(3)mbt-depleted S2 cells show a reduction of more than 60% of bulk monomethylated H4K20 (H4K20me1) while viability is barely affected. Ploidy and basic chromatin structure show only small changes in PR-Set7-depleted cells, but higher order interphase chromatin organization is significantly affected presumably resulting in the activation of the DNA damage checkpoint. In the absence of any other known functions of PR-Set7, the setting of the de novo monomethyl mark appears essential for cell viability in the presence or absence of the DNA damage checkpoint, but once newly assembled chromatin is established the monomethyl mark, protected by L(3)mbt, is dispensable

Analysis of the TCR Repertoire in HIV-Exposed but Uninfected Infants

Maternal human immunodeficiency virus (HIV) infection has been shown to leave profound and lasting impacts on the HIV-exposed uninfected (HEU) infant, including increased mortality and morbidity, immunological changes, and developmental delays compared to their HIV-unexposed (HU) counterparts. Exposure to HIV or antiretroviral therapy may influence immune development, which could increase morbidity and mortality. However, a direct link between the increased mortality and morbidity and the infant’s immune system has not been identified. To provide a global picture of the neonatal T cell repertoire in HEU versus HU infants, the diversity of the T cell receptor beta chain (TRB) expressed in cord blood samples from HEU infants was determined using next-generation sequencing and compared to healthy (HU) infants collected from the same community. While the TRB repertoire of HU infants was broadly diverse, in line with the expected idea of a naïve T cell repertoire, samples of HEU infants showed a significantly reduced TRB diversity. This study is the first to demonstrate differences in TRB diversity between HEU and HU cord blood samples and provides evidence that maternal HIV, in the absence of transmission, influences the adaptive immune system of the unborn child

Dynamical Instabilities of the Randall-Sundrum Model

We derive dynamical equations to describe a single 3-brane containing fluid matter and a scalar field coupling to the dilaton and the gravitational field in a five dimensional bulk. First, we show that a scalar field or an arbitrary fluid on the brane cannot evolve to cancel the cosmological constant in the bulk. Then we show that the Randall-Sundrum model is unstable under small deviations from the fine-tuning between the brane tension and the bulk cosmological constant and even under homogeneous gravitational perturbations. Implications for brane world cosmologies are discussed.Comment: 12 pages, 2 figure

Neutropenia in Barth syndrome:characteristics, risks, and management

PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices

Knowledge, Attitudes, and Practices of Poultry Farmers on Antimicrobial Use and Resistance in Kitwe, Zambia: Implications on Antimicrobial Stewardship

The inappropriate antimicrobial usage (AMU) in chicken production has led to an increase in the prevalence of antimicrobial resistance (AMR). In Zambia, there is little information documented regarding the knowledge, attitude, and practices of poultry farmers on AMU and AMR. Therefore, this study assessed the knowledge, attitude and practices regarding AMU and AMR among poultry farmers in Kitwe, Zambia. Methods: This was a cross-sectional study conducted among 106 poultry farmers from November to December 2021 using a structured questionnaire. Data analysis was done using IBM Statistical Package for Social Sciences (SPSS) version 26. Results: Overall, of the 106 participants, 90.6% knew what antimicrobials were, but only 29.2% were aware of AMR. The study showed that 46.2% of the participants had low knowledge, 71.7% had negative attitudes, and 61.3% had poor practices regarding AMR. The prevalence of antibiotic use in poultry production was 83%. The most used antimicrobials were tetracycline (84%) and gentamicin (35.2%). The commonly reported reason for the use of antimicrobials was for the treatment (93.2%) and prevention (89.8%) of diseases. Further, 76.9% of the administered antimicrobials were usually done without veterinarian consultation or prescription. Conclusion: The study shows that there was high AMU in poultry farms in Kitwe. However, there was low knowledge, negative attitude, and poor practices towards AMU and AMR. Therefore, there is a need for educational and sensitisation programmes regarding AMU and AMR among poultry farmers in Kitwe, Zambia. Alongside this, antimicrobial stewardship and surveillance systems should be strengthened in the livestock production sector. This will ensure food safety and public health

Knowledge and practices toward COVID-19 among healthcare students: A cross-sectional study at the University of Zambia

BACKGROUND: The COVID-19 pandemic led to the disruption of physical classes for university students globally, as large gatherings fuelled the transmission of the virus. In the efforts to mitigate its transmission and return to normality, prevention measures, including vaccination, have been encouraged. Therefore, it is critical to understand the knowledge and practices of students regarding COVID-19. This study assessed the knowledge and practices toward COVID-19 among healthcare students at the University of Zambia. MATERIALS AND METHODS: This questionnaire-based cross-sectional study was carried out from August 2021 to October 2021 among 478 healthcare students (pharmacy, physiotherapy, nursing, biomedical, medicine, and radiography). We used a previously validated questionnaire to measure knowledge and practice. The predictors of knowledge and practices were assessed using logistic regression with robust estimation of standard errors. Statistical analysis was conducted using Stata/BE version 17.0. RESULTS: Of the 478 respondents, 243 (50.8%) were females. A larger proportion, 175 (36.6%) were in Pharmacy training, and 156 (32.6%) were in their fifth year of study. The overall mean knowledge score of the participants was 87.9 (SD = 16.1), being higher at 89.6 (SD = 14.3) among medical students and the lowest at 86.7 (SD = 17.1) among Pharmacy students, although this was statistically non-significant (p = 0.488). The overall mean practice score was 60.0 (SD = 24.7), being significantly higher at 63.5 (23.4) among nursing, physiotherapy and environmental students compared to other students (p = 0.048). In multivariable analysis, the participant training program was non-significantly associated with knowledge and practice toward COVID-19. However, increased age (AOR = 1.09, 95% CI: 1.01-1.117) and residing in urban areas (AOR = 1.79, 95% CI: 1.07-3.01) than in rural areas were associated with higher odds of good practice toward COVID-19. CONCLUSION: The healthcare students generally showed good knowledge levels and poor practices toward COVID-19. Further, there was no evidence of a difference in knowledge of COVID-19 among healthcare students. These findings suggest the need for implementation strategies to be centered on improving the practices of students toward COVID-19