Nurturing diversity and inclusion in AI in Biomedicine through a virtual summer program for high school students

Artificial Intelligence (AI) has the power to improve our lives through a wide variety of applications, many of which fall into the healthcare space; however, a lack of diversity is contributing to limitations in how broadly AI can help people. The UCSF AI4ALL program was established in 2019 to address this issue by targeting high school students from underrepresented backgrounds in AI, giving them a chance to learn about AI with a focus on biomedicine, and promoting diversity and inclusion. In 2020, the UCSF AI4ALL three-week program was held entirely online due to the COVID-19 pandemic. Thus, students participated virtually to gain experience with AI, interact with diverse role models in AI, and learn about advancing health through AI. Specifically, they attended lectures in coding and AI, received an in-depth research experience through hands-on projects exploring COVID-19, and engaged in mentoring and personal development sessions with faculty, researchers, industry professionals, and undergraduate and graduate students, many of whom were women and from underrepresented racial and ethnic backgrounds. At the conclusion of the program, the students presented the results of their research projects at the final symposium. Comparison of pre- and post-program survey responses from students demonstrated that after the program, significantly more students were familiar with how to work with data and to evaluate and apply machine learning algorithms. There were also nominally significant increases in the students’ knowing people in AI from historically underrepresented groups, feeling confident in discussing AI, and being aware of careers in AI. We found that we were able to engage young students in AI via our online training program and nurture greater diversity in AI. This work can guide AI training programs aspiring to engage and educate students entirely online, and motivate people in AI to strive towards increasing diversity and inclusion in this field.     

CEP11004, a novel inhibitor of the mixed lineage kinases, suppresses apoptotic death in dopamine neurons of the substantia nigra induced by 6-hydroxydopamine

There is much evidence that the kinase cascade which leads to the phosphorylation of c-jun plays an important signaling role in the mediation of programmed cell death. We have previously shown that c-jun is phosphorylated in a model of induced apoptotic death in dopamine neurons of the substantia nigra in vivo. To determine the generality and functional significance of this response, we have examined c-jun phosphorylation and the effect on cell death of a novel mixed lineage kinase inhibitor, CEP11004, in the 6-hydroxydopamine model of induced apoptotic death in dopamine neurons. We found that expression of total c-jun and Ser73-phosphorylated c-jun is increased in this model and both colocalize with apoptotic morphology. CEP11004 suppresses apoptotic death to levels of 44 and 58% of control values at doses of 1.0 and 3.0 mg/kg, respectively. It also suppresses, to approximately equal levels, the number of profiles positive for the activated form of capase 9. CEP11004 markedly suppresses striatal dopaminergic fiber loss in these models, to only 22% of control levels. We conclude that c-jun phosphorylation is a general feature of apoptosis in living dopamine neurons and that the mixed lineage kinases play a functional role as up-stream mediators of cell death in these neurons.     

Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins

Elevated intracellular levels of dNTPs have been shown to be a biochemical marker of cancer cells. Recently, a series of mutations in the multifunctional dNTP triphosphohydrolase (dNTPase), sterile alpha motif and histidine–aspartate domain–containing protein 1 (SAMHD1), have been reported in various cancers. Here, we investigated the structure and functions of SAMHD1 R366C/H mutants, found in colon cancer and leukemia. Unlike many other cancer-specific mutations, the SAMHD1 R366 mutations do not alter cellular protein levels of the enzyme. However, R366C/H mutant proteins exhibit a loss of dNTPase activity, and their X-ray structures demonstrate the absence of dGTP substrate in their active site, likely because of a loss of interaction with the γ-phosphate of the substrate. The R366C/H mutants failed to reduce intracellular dNTP levels and restrict HIV-1 replication, functions of SAMHD1 that are dependent on the ability of the enzyme to hydrolyze dNTPs. However, these mutants retain dNTPase-independent functions, including mediating dsDNA break repair, interacting with CtIP and cyclin A2, and suppressing innate immune responses. Finally, SAMHD1 degradation in human primary-activated/dividing CD4+ T cells further elevates cellular dNTP levels. This study suggests that the loss of SAMHD1 dNTPase activity induced by R366 mutations can mechanistically contribute to the elevated dNTP levels commonly found in cancer cells.     

Health and Human Rights in Eastern Myanmar after the Political Transition: A Population-Based Assessment Using Multistaged Household Cluster Sampling

BackgroundMyanmar transitioned to a nominally civilian parliamentary government in March 2011. Qualitative reports suggest that exposure to violence and displacement has declined while international assistance for health services has increased. An assessment of the impact of these changes on the health and human rights situation has not been published.ConclusionThis large survey of health and human rights demonstrates that two years after political transition, vulnerable populations of eastern Myanmar are less likely to experience human rights violations compared to previous surveys. However, access to health services remains constrained, and risk of disease and death remains higher than the country as a whole. Efforts to address these poor health indicators should prioritize support for populations that remain outside the scope of most formal government and donor programs.     

Health and Human Rights in Karen State,Eastern Myanmar

Background

Decades of conflict in eastern Myanmar have resulted in high prevalence of human rights violations and poor health outcomes. While recent ceasefire agreements have reduced conflict in this area, it is unknown whether this has resulted in concomitant reductions in human rights violations.

Methods and Findings

We conducted a two-stage cluster survey of 686 households in eastern Myanmar to assess health status, access to healthcare, food security, exposure to human rights violations and identification of alleged perpetrators over the 12 months prior to January 2012, a period of near-absence of conflict in this region. Household hunger (FANTA-2 scale) was moderate/high in 91 (13.2%) households, while the proportion of households reporting food shortages in each month of 2011 ranged from 19.9% in December to 47.0% in September, with food insecurity peaking just prior to the harvest. Diarrhea prevalence in children was 14.2% and in everyone it was 5.8%. Forced labor was the most common human rights violation (185 households, 24.9%), and 210 households (30.6%) reported experiencing one or more human rights violations in 2011. Multiple logistic regression analysis identified associations between human rights violations and poor health outcomes.

Conclusion

Human rights violations and their health consequences persist despite reduced intensity of conflict in eastern Myanmar. Ceasefire agreements should include language that protects human rights, and reconciliation efforts should address the health consequences of decades of human rights violations.     

Isolation of Butyl 2,3‐Dihydroxybenzoate From Paenibacillus elgii HOA73 Against Fusarium oxysporum f.sp. Lycopersici

Here we report for the first time the isolation of butyl 2,3‐dihydroxybenzoate (B2,3DB) from the novel antagonistic bacterium Paenibacillus elgii HOA73 and its activity against Fusarium oxysporum f.sp. lycopersici (FOL). In this study, the bacterial strain P. elgii HOA73 was isolated from soil and identified via 16S rRNA gene sequence analysis. The isolate demonstrated significant antagonism towards several plant pathogens including FOL. Our results showed the bacterial culture filtrate of P. elgii HOA73 to be highly active, inhibiting 86.1% of the growth of FOL at 50% concentration. Similarly, the bacterial crude extract of P. elgii HOA73 at 2 mg significantly inhibited FOL growth by 72.5%. An antifungal compound was purified from the bacterial crude extract of P. elgii HOA73 through different chromatographic techniques and was identif‐ied as butyl 2,3‐dihydroxybenzoate (B2,3DB) based on nuclear magnetic resonance and liquid chromatography‐mass spectrometry analyses. B2,3DB displayed potent antifungal properties, inhibiting FOL growth by 83.2% when used at 0.6 mg. The minimum inhibitory concentration of B2,3DB to inhibit any visible mycelial growth of FOL was 32 μg ml^?1. All FOL conidia displayed an absence of germination or degradation when treated with 32 μg ml^?1 B2,3DB after 8 or 24 h, respectively. Therefore, our results clearly demonstrated B2,3DB, as well as P. elgii HOA73, as potential biological control agents for the management of FOL.     

In vitro induction of tetraploids in an interspecific hybrid of Calanthe (Calanthe discolor × Calanthe sieboldii) through colchicine and oryzalin treatments

Tetraploids were successfully produced from diploid seeds obtained through interspecific crossing between Calanthe discolor and Calanthe sieboldii by treating with colchicine or oryzalin. Colchicine was tested at concentrations of 0.05 and 0.1 % for 0, 3, or 7 days and oryzalin was tested at a concentration of 0.003 % for 1, 2, 4, and 7 days, and the ploidy of the seedlings was determined by flow cytometry. Tetraploids (4×) were obtained from the interspecific hybrid seeds treated with all colchicine and oryzalin concentrations. The most efficient condition for inducing tetraploids seemed to be treated with 0.003 % oryzalin for 1 or 2 days. Cytological and morphological evidence confirmed the results of flow cytometric analysis. The stomatal density and sizes of the tetraploid plants were significantly higher and larger than those of the diploid plants. Differences in leaf shape were found between the tetraploid and diploid plants under the same growing conditions: the leaves of the diploids were elongated and those of the tetraploids were round.     

A novel design of bioartificial kidneys with improved cell performance and haemocompatibility

Treatment with bioartificial kidneys had beneficial effects in animal experiments and improved survival of critically ill patients with acute kidney injury in a Phase II clinical trial. However, a Phase II b clinical trial failed. This and other results suggested various problems with the current design of bioartificial kidneys. We propose a novel design to improve various properties of device, including haemocompatibility and cell performance. An important feature of the novel design is confinement of the blood to the lumina of the hollow fibre membranes. This avoids exposure of the blood to the non‐haemocompatible outer surfaces of hollow fibre membranes, which usually occurs in bioartificial kidneys. We use these outer surfaces as substrate for cell growth. Our results show that commercial hollow fibre membranes can be directly applied in the bioreactor when human primary renal proximal tubular cells are grown in this configuration, and no coatings are required for the formation of robust and functional renal epithelia. Furthermore, we demonstrate that the bioreactor unit produces significant amounts of interleukins. This result helps to understand the immunomodulatory effects of bioartificial kidneys, which have been observed previously. The novel bioartificial kidney design outlined here and the results obtained would be expected to improve the safety and performance of bioartificial kidneys and to contribute to a better understanding of their effects.     

Three-dimensional culture and bioreactors for cellular therapies

A bioreactor is defined as a specifically designed vessel to facilitate the growth of organisms and cells through application of physical and/or electrical stimulus. When cells with therapeutic potential were first discovered, they were initially cultured and expanded in two-dimensional (2-D) culture vessels such as plates or T-flasks. However, it was soon discovered that bioreactors could be used to expand and maintain cultures more easily and efficiently. Since then, bioreactors have come to be accepted as an indispensable tool to advance cell and tissue culture further. A wide array of bioreactors has been developed to date, and in recent years businesses have started supplying bioreactors commercially. Bioreactors in the research arena range from stirred tank bioreactors for suspension culture to those with various mechanical actuators that can apply different fluidic and mechanical stresses to tissues and three-dimensional (3-D) scaffolds. As regenerative medicine gains more traction in the clinic, bioreactors for use with cellular therapies are being developed and marketed. While many of the simpler bioreactors are fit for purpose, others fail to satisfy the complex requirements of tissues in culture. We have examined the use of different types of bioreactors in regenerative medicine and evaluated the application of bioreactors in the realization of emerging cellular therapies.