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1.
J Acquir Immune Defic Syndr ; 94(2S): S93-S98, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37707855

RESUMO

BACKGROUND: The Miami-CFAR Diversity, Equity & Inclusion Pathway Initiative (Miami CDEIPI) is designed to promote a diverse scientific workforce that reflects the communities at the highest risk of HIV in South Florida. SETTING AND METHODS: The focus of the Miami CDEIPI is to help train the next generation of Underrepresented Minorities (URM) and Black, Indigenous, People of Color (BIPOC) in HIV/AIDS-related research through a team science experience. The Miami CDEIPI objectives are to facilitate the interaction of URM/BIPOC students with the network of CFAR-affiliated investigators and to enable these students to access the cutting-edge technologies at the Miami-CFAR and the Sylvester Comprehensive Cancer Center and other resources at the University of Miami. RESULTS: Five URM/BIPOC students supported by the program in year 1 have been carrying out projects in collaboration with mentors at their parent institution and Miami-CFAR investigators. The students used the state-of-the-art laboratories and core facilities. They began their research with a proposal designed to integrate the cutting-edge technologies now available to them. Their training included participation in Miami-CFAR-sponsored activities such as seminars, an annual conference, and a national HIV workshop. Candidates in the Miami CDEIPI are in the process of developing their research proposals, integrating cutting-edge technologies into their doctoral dissertation research. Their projects are now in the completion phase. CONCLUSIONS: The Miami CDEIPI focuses its resources on one of the conspicuous gaps in the career paths of URM/BIPOC researchers-the dearth of leading URM/BIPOC scientists in the field. The Miami CDEIPI provides a professional network that supports the participation of URM/BIPOC trainees in innovative research and career skill training.


Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Pesquisa Interdisciplinar , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Estudantes , Florida
2.
J Med Virol ; 95(1): e28314, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36380418

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG with 2-fluoro-deoxy- d-glucose, a glycolysis inhibitor, and 2-deoxy-fluoro- d-mannose (2-DFM), a specific N-glycosylation inhibitor. At doses similar to those clinically achievable with 2-DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2-DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2-DFM, we found that d-mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N-glycosylation is the main antiviral target using d-mannose competition experiments. Suppression of N-glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV-induced inhibition of the protein kinase R-like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV-induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N-glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs.


Assuntos
COVID-19 , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Herpesvirus Humano 8/fisiologia , Manose/farmacologia , Glucose , Glicosilação , Resposta a Proteínas não Dobradas , Replicação Viral , Antivirais/farmacologia
3.
mSphere ; 5(1)2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051238

RESUMO

The lysosome-like vacuolar compartment (VAC) is a major site of proteolysis in the intracellular parasite Toxoplasma gondii Previous studies have shown that genetic ablation of a VAC-residing cysteine protease, cathepsin protease L (CPL), resulted in the accumulation of undigested protein in the VAC and loss of parasite viability during the chronic stage of infection. However, since the maturation of another VAC localizing protease, cathepsin protease B (CPB), is dependent on CPL, it remained unknown whether these defects result directly from ablation of CPL or indirectly from a lack of CPB maturation. Likewise, although a previously described cathepsin D-like aspartyl protease 1 (ASP1) could also play a role in proteolysis, its definitive residence and function in the Toxoplasma endolysosomal system were not well defined. Here, we demonstrate that CPB is not necessary for protein turnover in the VAC and that CPB-deficient parasites have normal growth and viability in both the acute and chronic stages of infection. We also show that ASP1 depends on CPL for correct maturation, and it resides in the T. gondii VAC, where, similar to CPB, it plays a dispensable role in protein digestion. Taken together with previous work, our findings suggest that CPL is the dominant protease in a hierarchy of proteolytic enzymes within the VAC. This unusual lack of redundancy for CPL in T. gondii makes it a single exploitable target for disrupting chronic toxoplasmosis.IMPORTANCE Roughly one-third of the human population is chronically infected with the intracellular single-celled parasite Toxoplasma gondii, but little is known about how this organism persists inside people. Previous research suggested that a parasite proteolytic enzyme, termed cathepsin protease L, is important for Toxoplasma persistence; however, it remained possible that other associated proteolytic enzymes could also be involved in the long-term survival of the parasite during infection. Here, we show that two proteolytic enzymes associated with cathepsin protease L play dispensable roles and are dependent on cathepsin L to reach maturity, which differs from the corresponding enzymes in humans. These findings establish a divergent hierarchy of proteases and help focus attention principally on cathepsin protease L as a potential target for interrupting Toxoplasma chronic infection.


Assuntos
Ácido Aspártico Proteases/metabolismo , Catepsina B/metabolismo , Lisossomos/metabolismo , Proteínas de Protozoários/metabolismo , Toxoplasma/enzimologia , Humanos , Estágios do Ciclo de Vida , Proteólise , Toxoplasma/crescimento & desenvolvimento , Vacúolos/metabolismo
4.
Diving Hyperb Med ; 42(4): 195-200, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23258455

RESUMO

BACKGROUND: The American Academy of Underwater Science (AAUS) constitutes the single largest pool of organizations with scientific diving programmes in North America. Members submit annual summaries of diving activity and any related incidents. METHODS: All diving records for a 10-year period between January 1998 and December 2007 were reviewed. Incidents were independently classified or reclassified by a four-person panel with expertise in scientific diving and diving safety using a previously published protocol. Subsequent panel discussion produced a single consensus classification of each case. RESULTS: A total of 95 confirmed incidents were reported in conjunction with 1,019,159 scientific dives, yielding an overall incidence of 0.93/10,000 person-dives. A total of 33 cases were determined to involve decompression illness (DCI), encompassing both decompression sickness and air embolism. The incidence of DCI was 0.324/10,000 person-dives, substantially lower than the rates of 0.9-35.3/10,000 published for recreational, instructional/guided, commercial and/or military diving. CONCLUSIONS: Scientific diving safety may be facilitated by a combination of relatively high levels of training and oversight, the predominance of shallow, no-decompression diving and, possibly, low pressure to complete dives under less than optimal circumstances.


Assuntos
Doença da Descompressão/epidemiologia , Mergulho/estatística & dados numéricos , Embolia Aérea/epidemiologia , Traumatismos Ocupacionais/epidemiologia , Pesquisa/estatística & dados numéricos , Doença da Descompressão/classificação , Mergulho/lesões , Humanos , Incidência , Traumatismos Ocupacionais/classificação , Segurança , Sociedades/estatística & dados numéricos , Estados Unidos/epidemiologia
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