Biology subjects

Lemos, C.

Publications and source records attributed to Lemos, C..

7 recordsLinked to original sources

bioRxiv2024

Rac1 inhibition prevents axonal cytoskeleton dysfunction in Transthyretin Amyloid Polyneuropathy

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic TTR, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy with autonomic dysfunction. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knock-in mice. Proteomics of hTTRA97S sural nerves revealed dysregulation of actin-related proteins. hTTRA97S DRG neurons presented a defective actin distribution in growth cones along with a reduction in axonal actin trails, and an associated impairment in the pool of pre-synaptic vesicles. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Importantly, cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation in DRG neurites and sciatic nerves of pre-symptomatic mice. Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. Remarkably, in ATTRv-PN patients with late-onset disease, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonal degeneration in ATTRv-PN and highlight Rac1 as a promising therapeutic target.

neuroscience↗

bioRxiv2019

Microtubule tyrosination/detyrosination specifies a mitotic error code

Incorrect kinetochore-microtubule attachments during mitosis can lead to chromosomal instability, a hallmark of human cancers. Mitotic error correction relies on the kinesin-13 MCAK, a microtubule depolymerase whose activity in vitro is suppressed by -tubulin detyrosination - a post-translational modification enriched on long-lived microtubules. However, whether and how MCAK activity required for mitotic error correction is regulated by microtubule tyrosination/detyrosination remains unknown. Here we found that microtubule detyrosination accumulates on correct, more stable, kinetochore-microtubule attachments, whereas constitutively high microtubule detyrosination near kinetochores compromised efficient error correction. Rescue experiments suggest that mitotic errors due to excessive microtubule detyrosination result from suppression of MCAK activity, without globally affecting kinetochore microtubule half-life. Importantly, MCAK centromeric activity was required and sufficient to rescue mitotic errors due to excessive microtubule detyrosination. Thus, microtubules are not just passive elements during mitotic error correction, and their tyrosination/detyrosination works as a mitotic error code that allows centromeric MCAK to discriminate correct and incorrect kinetochore-microtubule attachments, thereby promoting mitotic fidelity.

cell biology↗

bioRxiv2018

Emergence of the East-Central-South-African genotype of Chikungunya virus in Brazil and the city of Rio de Janeiro may have occurred years before surveillance detection

Brazil, which is hyperendemic for dengue virus (DENV), has had recent Zika (ZIKV) and (CHIKV) Chikungunya virus outbreaks. Since March 2016, CHIKV is the arbovirus infection most frequently diagnosed in Rio de Janeiro. In the analysis of 1835 syndromic patients, screened by real time RT-PCR, 56.4% of the cases were attributed to CHIKV, 29.6% to ZIKV, and 14.1% to DENV-4. Sequence analyses of CHIKV from sixteen samples revealed that the East-Central-South-African (ECSA) genotype of CHIKV has been circulating in Brazil since 2013 [95% bayesian credible interval (BCI): 03/2012-10/2013], almost a year before it was detected by arbovirus surveillance program. Brazilian cases are related to Central African Republic sequences from 1980s. To the best of our knowledge, given the available sequence published here and elsewhere, the ECSA genotype was likely introduced to Rio de Janeiro early on 2014 (02/2014; BCI: 07/2013-08/2014) through a single event, after primary circulation in the Bahia state at the Northestern Brazil in the previous year. The observation that the ECSA genotype of CHIKV was circulating undetected underscores the need for improvements in molecular methods for viral surveillance.

genomics↗

bioRxiv2018

CD44v6 expression is a novel predictive marker of therapy response and poor prognosis in gastric cancer patients

Late diagnosis, modest treatment options and lack of predictive markers of therapy response dictate the poor overall survival (OS) of [~]1 year in most gastric cancer (GC) patients. We hypothesized that the level of CD44v6 expression in tumor cells could predict therapy response and prognosis in GC patients.\n\nWe analyzed a surgical tumor series of GC patients for the extension of CD44v6 membranous immuno-expression, clinical-pathological features, patient survival, and response to therapy. By integrating this information, we assessed the value of CD44v6 expression to predict benefit from current treatment regimens and prognosis in GC patients. We used GC cell lines and mouse xenografts to assess and/validate the biological impact of CD44v6 expression in GC cells behavior.\n\nWe demonstrated that GC patients whose tumors present higher levels of CD44v6 membranous expression benefit from adding chemotherapy to surgery as opposed to those without CD44v6 expression. Moreover, patients bearing CD44_high tumors presented worse OS than those bearing CD44_absent/low tumors, consolidating the role of CD44v6 expression as an independent factor of poor prognosis in this disease. Finally, our in vitro and patients data pinpoints the CD44v6+ cell population as the driver of tumor recurrence following conventional chemotherapy, in heterogeneous tumors composed by CD44v6- and CD44v6+ cells.\n\nOur study pioneers the identification of CD44v6 as a potential predictive marker of response to conventional chemotherapy, and consolidates CD44v6 as an independent marker of poor prognosis in GC. Overall, our data strongly supports selection of patients with high CD44v6 expressing tumors for conventional chemotherapy with or without surgery, regardless of the TNM stage.

cancer biology↗

bioRxiv2018

How Public Transport affected the Propagation of Zika and Microcephaly within Rio de Janeiro early in 2015

From mid-2015 to the end of January 2016, 47 cases of microcephaly were observed in the city of Rio de Janeiro, that were not due to other viral infections (syphilis, toxoplasmosis, herpes & cytomegalovirus). These children were conceived from Dec 2014 to April 2015, far too early to be explained by the officially recorded cases from October 2015 onward. Zika must have been rampant in the city from late 2014 onward. In the first half of the paper we study how the geographic spread of microcephaly cases evolved from mid-2015 to January 2016 (and hence Zika 6-9 months earlier). Cases were not evenly spread in proportion to the number of births; they were preferentially located in the northern suburbs apparently following the public transport routes, with virtually no cases in favelas and none in the southern suburbs (Zona Sul). One key difference between the transport systems in the northern and southern suburbs is that the metro & rail system in the north is above ground in the north whereas in the southern part the metro is underground with air-conditioning in carriages and forced ventilation on the platforms. The train system does not extend to Zona Sul.\n\nIn the second half of the paper we postulate that the air-conditioning and ventilation prevent mosquitos from biting people who are waiting on platforms in Zona Sul. Agent-based simulations are used to test this hypothesis. After confirming this, we postulate that providing air-conditioning and/or forced ventilation on the rail-metro transport hub in the city center (Centro) would significantly delay the propagation of arboviruses in the city, possibly preventing epidemics. One advantage of this proposal is that it does not require the use of insecticides.

epidemiology↗

bioRxiv2017

Zika: An ongoing threat to women and infants

Recent data from Rio de Janeiro shows a sharp drop in the number of notified cases of Zika in the summer of 2016-17, compared to the previous summer. This is probably due to herd immunity built up after the previous year's epidemic. There is still a much higher incidence among women than men, almost certainly due to sexual transmission. An unexpected feature of the new data is that there are proportionally far more cases in children under 15 months than in older age classes. By comparing the incidence for 2016-17 with that of 2015-16, we can deduce the proportion of reported cases for men and women, and also verify that the disparity of incidence between them is still present. Women and children still represent risk groups with regard to Zika infection, even during a non-epidemic season.

epidemiology↗

bioRxiv2017

Can Zika Account For The Missing Babies?

The Zika virus (ZIKV) spread rapidly in Brazil in 2015 and 2016. Rio de Janeiro was among the Brazilian cities which were hit the hardest, with more that a hundred thousand confirmed cases up to the end of 2016. Given the severity of the neurological damage caused by ZIKV on fetuses, we wondered whether it would also cause an increase in the number of miscarriages, especially very early ones. As early miscarriages are unlikely to be recorded as a health event, this effect - if it occurred - would only show up as a reduction in the number of live births. In this paper we show that there was a 15% drop in live births between September and December 2016 compared to the previous year, and that this sharp drop from epidemiological week 33 onward is strongly correlated with the number of recorded cases of Zika about 40 weeks earlier. We postulate that ZIKV is directly responsible for this drop in the birth rate. Further work is required to ascertain whether other factors such the fear of having a microcephaly baby or the economic crisis are having a significant effect.

epidemiology↗