14 research outputs found
Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures
The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals
Randomness Concerns When Deploying Differential Privacy
The U.S. Census Bureau is using differential privacy (DP) to protect
confidential respondent data collected for the 2020 Decennial Census of
Population & Housing. The Census Bureau's DP system is implemented in the
Disclosure Avoidance System (DAS) and requires a source of random numbers. We
estimate that the 2020 Census will require roughly 90TB of random bytes to
protect the person and household tables. Although there are critical
differences between cryptography and DP, they have similar requirements for
randomness. We review the history of random number generation on deterministic
computers, including von Neumann's "middle-square" method, Mersenne Twister
(MT19937) (previously the default NumPy random number generator, which we
conclude is unacceptable for use in production privacy-preserving systems), and
the Linux /dev/urandom device. We also review hardware random number generator
schemes, including the use of so-called "Lava Lamps" and the Intel Secure Key
RDRAND instruction. We finally present our plan for generating random bits in
the Amazon Web Services (AWS) environment using AES-CTR-DRBG seeded by mixing
bits from /dev/urandom and the Intel Secure Key RDSEED instruction, a
compromise of our desire to rely on a trusted hardware implementation, the
unease of our external reviewers in trusting a hardware-only implementation,
and the need to generate so many random bits.Comment: 12 pages plus 2 pages bibliograph
Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations
Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and –negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n=1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection
Erasing Sensorimotor Memories via PKMζ Inhibition
Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMζ). Whereas the role of PKMζ in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMζ inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training. The rate of relearning the task after the memory disruption by ZIP was indistinguishable from the rate of initial learning, suggesting no significant savings after the memory loss. These results indicate a shared molecular mechanism of storage for declarative and procedural forms of memory
Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures
The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals
Health Professional Training and Capacity Strengthening Through International Academic Partnerships: The First Five Years of the Human Resources for Health Program in Rwanda
Abstract
Background: The Rwanda Human Resources for Health Program (HRH Program) is a 7-year (2012-2019) health
professional training initiative led by the Government of Rwanda with the goals of training a large, diverse, and competent
health workforce and strengthening the capacity of academic institutions in Rwanda.
Methods: The data for this organizational case study was collected through official reports from the Rwanda Ministry of
Health (MoH) and 22 participating US academic institutions, databases from the MoH and the College of Medicine and
Health Sciences (CMHS) in Rwanda, and surveys completed by the co-authors.
Results: In the first 5 years of the HRH Program, a consortium of US academic institutions has deployed an average of 99
visiting faculty per year to support 22 training programs, which are on track to graduate almost 4600 students by 2019.
The HRH Program has also built capacity within the CMHS by promoting the recruitment of Rwandan faculty and the
establishment of additional partnerships and collaborations with the US academic institutions.
Conclusion: The milestones achieved by the HRH Program have been substantial although some challenges persist.
These challenges include adequately supporting the visiting faculty; pairing them with Rwandan faculty (twinning);
ensuring strong communication and coordination among stakeholders; addressing mismatches in priorities between
donors and implementers; the execution of a sustainability strategy; and the decision by one of the donors not to renew
funding beyond March 2017. Over the next 2 academic years, it is critical for the sustainability of the 22 training programs
supported by the HRH Program that the health-related Schools at the CMHS significantly scale up recruitment of new
Rwandan faculty. The HRH Program can serve as a model for other training initiatives implemented in countries affected
by a severe shortage of health professionals
Correction: Experiences of doctoral students enrolled in a research fellowship program to support doctoral training in Africa (2014 to 2018): The Consortium for Advanced Research Training in Africa odyssey.
[This corrects the article DOI: 10.1371/journal.pone.0252863.]