Closing the gaps in the continuum of depression care for persons with HIV: modeling the impact on viral suppression in the United States.

OBJECTIVE: Depression is prevalent among persons with HIV (PWH) and is associated with poorer adherence and lack of viral load suppression (VLS). When treated for depression, PWH are more likely to stay in HIV care and adhere to medications; however, for many PWH, depression is not adequately diagnosed or treated. We adapted Progression and Transmission of HIV (PATH 3.0), a U.S. agent-based dynamic stochastic simulation model, by incorporating a continuum of depression care and estimating the impact on VLS of an enhanced depression diagnosis and care scenario (EDC). METHODS: We compared EDC - whereby every PWH is assessed for depression, gets treatment if diagnosed, and of those, half achieve remission - to a status quo scenario (SQ) on VLS. Based on published findings, assumptions for SQ were: 34.7% depressed, 45% diagnosed, 55.3% treated and 33% of treated achieving remission. Compared to PWH without depression, we assumed the probability of being non-virally suppressed increased by 1.57 times for PWH with depression (PWH-D), and by 0.95 times for PWH with remitted depression. RESULTS: There was an average increase of 14.6% (11.5-18.5) in the proportion of PWH-D who achieved VLS in EDC compared to SQ. Among all PWH, there was a 4.7% (3.4-6.0) increase in the proportion who achieved VLS in EDC compared to SQ. CONCLUSIONS: Fully diagnosing and adequately treating depression would improve health and quality of life for a substantial proportion of PWH-D and result in a nearly 5% increase in expected rates of VLS in the United States, supporting national prevention goals.

Estimated Lifetime HIV-Related Medical Costs in the United States.

BACKGROUND: Lifetime cost estimates are a useful tool in measuring the economic burden of HIV in the United States. Previous estimation methods need to be updated, given improving antiretroviral therapy regimens and updated costs. METHODS: We used an updated version of the agent-based model progression and transmission of HIV (PATH) 3.0 to reflect current regimens and costs. We simulated a cohort of those infected in 2015 until the last person had died to track the lifetime costs for treatment of HIV, including HIV health care utilization costs (inpatient, outpatient, opportunistic infection prophylaxis, non-HIV medication, and emergency department), opportunistic infection treatment costs, and testing costs. We assumed a median per-person diagnosis delay of 3 years and a 3% base monthly probability of dropout from care for a base-case scenario. Additionally, we modeled a most favorable scenario (median diagnosis delay of 1 year and 1% base dropout rate) and a least favorable scenario (median diagnosis delay of 5 years and 5% base dropout rate). RESULTS: We estimated an average lifetime HIV-related medical cost for a person with HIV of $420,285 (2019 US$) discounted (3%) and $1,079,999 undiscounted for a median 3-year diagnosis delay and 3% base dropout rate. Our discounted cost estimate was $490,045 in our most favorable scenario and $326,411 in our least favorable scenario. CONCLUSIONS: Lifetime per-person HIV-related medical costs depend on the time from infection to diagnosis and the likelihood of dropping out of care. Our results, which are similar to previous studies, reflect updated antiretroviral therapy regimens and costs for HIV treatment.

An H3K9 methylation-dependent protein interaction regulates the non-enzymatic functions of a putative histone demethylase.

H3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that reverses epigenetic silencing. Here, we reveal an inversion of this paradigm where a putative histone demethylase Epe1 in fission yeast, has a non-enzymatic function that opposes heterochromatin assembly. Mutations within the putative catalytic JmjC domain of Epe1 disrupt its interaction with Swi6HP1 suggesting that this domain might have other functions besides enzymatic activity. The C-terminus of Epe1 directly interacts with Swi6HP1, and H3K9 methylation stimulates this protein-protein interaction in vitro and in vivo. Expressing the Epe1 C-terminus is sufficient to disrupt heterochromatin by outcompeting the histone deacetylase, Clr3 from sites of heterochromatin formation. Our results underscore how histone modifying proteins that resemble enzymes have non-catalytic functions that regulate the assembly of epigenetic complexes in cells.

A cell's identity depends on which of its genes are active. One way for cells to control this process is to change how accessible their genes are to the molecular machinery that switches them on and off. Special proteins called histones determine how accessible genes are by altering how loosely or tightly DNA is packed together. Histones can be modified by enzymes, which are proteins that add or remove specific chemical 'tags'. These tags regulate how accessible genes are and provide cells with a memory of gene activity. For example, a protein found in yeast called Epe1 helps reactivate large groups of genes after cell division, effectively 're-setting' the yeast's genome and eliminating past memories of the genes being inactive. For a long time, Epe1 was thought to do this by removing methyl groups, a 'tag' that indicates a gene is inactive, from histones ­ that is, by acting like an enzyme. However, no direct evidence to support this hypothesis has been found. Raiymbek et al. therefore set out to determine exactly how Epe1 worked, and whether or not it did indeed behave like an enzyme. Initial experiments testing mutant versions of Epe1 in yeast cells showed that the changes expected to stop Epe1 from removing methyl groups instead prevented the protein from 'homing' to the sections of DNA it normally activates. Detailed microscope imaging, using live yeast cells engineered to produce proteins with fluorescent markers, revealed that this inability to 'home' was due to a loss of interaction with Epe1's main partner, a protein called Swi6. This protein recognizes and binds histones that have methyl tags. Swi6 also acts as a docking site for proteins involved in deactivating genes in close proximity to these histones. Further biochemical studies revealed how the interaction between Epe1 and Swi6 can help in gene reactivation. The methyl tag on histones in inactive regions of the genome inadvertently helps Epe1 interact more efficiently with Swi6. Then, Epe1 can simply block every other protein that binds to Swi6 from participating in gene deactivation. This observation contrasts with the prevailing view where the active removal of methyl tags by proteins such as Epe1 switches genes from an inactive to an active state. This work shows for the first time that Epe1 influences the state of the genome through a process that does not involve enzyme activity. In other words, although the protein may 'moonlight' as an enzyme, its main job uses a completely different mechanism. More broadly, these results increase the understanding of the many different ways that gene activity, and ultimately cell identity, can be controlled.

Hsp90 Is Essential for Chl1-Mediated Chromosome Segregation and Sister Chromatid Cohesion.

Recent studies have demonstrated that aberrant sister chromatid cohesion causes genomic instability and hence is responsible for the development of a tumor. The Chl1 (chromosome loss 1) protein (homolog of human ChlRl/DDX11 helicase) plays an essential role in the proper segregation of chromosomes during mitosis. The helicase activity of Chl1 is critical for sister chromatid cohesion. Our study demonstrates that Hsp90 interacts with Chl1 and is necessary for its stability. We observe that the Hsp90 nonfunctional condition (temperature-sensitive iG170Dhsp82 strain at restrictive temperature) induces proteasomal degradation of Chl1. We have mapped the domains of Chl1 and identified that the presence of domains II, III, and IV is essential for efficient interaction with Hsp90. We have demonstrated that Hsp90 inhibitor 17-AAG (17-allylamino-geldenamycin) causes destabilization of Chl1 protein and enhances significant disruption of sister chromatid cohesion, which is comparable to that observed under the Δchl1 condition. Our study also revealed that 17-AAG treatment causes an increased frequency of chromosome loss to a similar extent as that of the Δchl1 cells. Hsp90 functional loss has been earlier linked to aneuploidy with very poor mechanistic insight. Our result identifies Chl1 as a novel client of Hsp90, which could be further explored to gain mechanistic insight into aneuploidy.IMPORTANCE Recently, Hsp90 functional loss has been linked to aneuploidy; however, until now none of the components of sister chromatid cohesion (SCC) have been demonstrated as the putative clients of Hsp90. In this study, we have established that Chl1, the protein which is involved in maintaining sister chromatid cohesion as well as in preventing chromosome loss, is a direct client of Hsp90. Thus, with understanding of the molecular mechanism, how Hsp90 controls the cohesion machinery might reveal new insights which can be exploited further for attenuation of tumorigenesis.

Impact of Improved HIV Care and Treatment on PrEP Effectiveness in the United States, 2016-2020.

BACKGROUND: The effect of improving diagnosis, care, and treatment of persons living with HIV (PLWH) on pre-exposure prophylaxis (PrEP) effectiveness in the United States has not been well established. METHODS: We used a dynamic, compartmental model that simulates the sexually active US population. We investigated the change in cumulative HIV incidence from 2016 to 2020 for 3 HIV care-continuum levels and the marginal benefit of PrEP compared with each. We also explored the marginal benefit of PrEP for individual risk groups, and as PrEP adherence, coverage and dropout rates varied. RESULTS: Delivering PrEP in 2016 to persons at high risk of acquiring HIV resulted in an 18.1% reduction in new HIV infections from 2016 to 2020 under current care-continuum levels. Achieving HIV national goals of 90% of PLWH with diagnosed infection, 85% of newly diagnosed PLWH linked to care at diagnosis, and 80% of diagnosed PLWH virally suppressed reduced cumulative incidence by 34.4%. Delivery of PrEP in addition to this scenario resulted in a marginal benefit of 11.1% additional infections prevented. When national goals were reached, PrEP prevented an additional 15.2% cases among men who have sex with men, 3.9% among heterosexuals, and 3.8% among persons who inject drugs. CONCLUSIONS: The marginal benefit of PrEP was larger when current HIV-care-continuum percentages were maintained but continued to be substantial even when national care goals were met. The high-risk men who have sex with men population was the chief beneficiary of PrEP.

Explicit Prejudice: Evidence from a New Survey.

A representative phone survey to study explicit prejudice against women and Dalits in Delhi, Mumbai, Uttar Pradesh, and Rajasthan reveals widespread prejudice in several domains and discusses the consequences for women and Dalits, and society as a whole. The results suggest the need for a more robust public discourse and active approach to measuring and challenging prejudice and discrimination.

Official government statistics of road traffic deaths in India under-represent pedestrians and motorised two wheeler riders.

BACKGROUND: Reliable data on traffic deaths are important for planning road safety programmes and evaluating progress. Although pedestrians comprise approximately 40% of traffic deaths in low-income and middle-income countries, official government statistics in India suggest that pedestrians comprise less than 10% of deaths. OBJECTIVE: To assess the accuracy of official tabulations of traffic deaths among various road users in India. METHOD: We reviewed police first information reports (FIRs) of traffic deaths in one district (Belgaum) in 2013 and 2014 and extracted information about crash victims. We validated the FIRs by linking with case files from four police stations in the district. Finally, we compared the information on types of road users killed based on FIRs with the district's official tabulations. RESULTS: We found that the distribution of deaths by types of road users reported in official tabulations differed substantially from the underlying police reports. While official tabulations reported that only 9% of deaths in 2013 were pedestrians and 37% were riders of motorised two wheelers, FIRs showed that these groups accounted for 21% and 49% of deaths, respectively. DISCUSSION: Official tabulations of traffic deaths in India do not correctly represent the types of roads users killed. Until the Indian National Crime Records Bureau has corrected the process of generating statistical tabulations from police reports, data on the types of road users killed in India should not be used for research and policy. In the interim, researchers and policy makers who need such information should extract it from police case files.

Hsp90 induces increased genomic instability toward DNA-damaging agents by tuning down RAD53 transcription.

It is well documented that elevated body temperature causes tumors to regress upon radiotherapy. However, how hyperthermia induces DNA damage sensitivity is not clear. We show that a transient heat shock and particularly the concomitant induction of Hsp90 lead to increased genomic instability under DNA-damaging conditions. Using Saccharomyces cerevisiae as a model eukaryote, we demonstrate that elevated levels of Hsp90 attenuate efficient DNA damage signaling and dictate preferential use of the potentially mutagenic double-strand break repair pathway. We show that under normal physiological conditions, Hsp90 negatively regulates RAD53 transcription to suppress DNA damage checkpoint activation. However, under DNA damaging conditions, RAD53 is derepressed, and the increased level of Rad53p triggers an efficient DNA damage response. A higher abundance of Hsp90 causes increased transcriptional repression on RAD53 in a dose-dependent manner, which could not be fully derepressed even in the presence of DNA damage. Accordingly, cells behave like a rad53 loss-of-function mutant and show reduced NHEJ efficiency, with a drastic failure to up-regulate RAD51 expression and manifestly faster accumulation of CLN1 and CLN2 in DNA-damaged G1, cells leading to premature release from checkpoint arrest. We further demonstrate that Rad53 overexpression is able to rescue all of the aforementioned deleterious effects caused by Hsp90 overproduction.

Hsp90, the concertmaster: tuning transcription.

In the last decade, Hsp90 has emerged as a major regulator of cancer cell growth and proliferation. In cancer cells, it assists in giving maturation to oncogenic proteins including several kinases and transcription factors (TF). Recent studies have shown that apart from its chaperone activity, it also imparts regulation of transcription machinery and thereby alters the cellular physiology. Hsp90 and its co-chaperones modulate transcription at least at three different levels. In the first place, they alter the steady-state levels of certain TFs in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression. In this review, we discuss the role of Hsp90 in all the three aforementioned mechanisms of transcriptional control, taking examples from various model organisms with a special emphasis on cancer progression.

Reduced transport of swimming particles in chaotic flow due to hydrodynamic trapping.

We computationally study the transport of active, self-propelled particles suspended in a two-dimensional chaotic flow. The pointlike, spherical particles have their own intrinsic swimming velocity, which modifies the dynamical system so that the particles can break the transport barriers present in the carrier flow. Surprisingly, we find that swimming does not necessarily lead to enhanced particle transport. Small but finite swimming speed can result in reduced transport, as swimmers get stuck for long times in traps that form near elliptic islands in the background flow. Our results have implications for models of transport and encounter rates for small marine organisms.